CA2178914A1 - Benzoylethylene derivative - Google Patents
Benzoylethylene derivativeInfo
- Publication number
- CA2178914A1 CA2178914A1 CA002178914A CA2178914A CA2178914A1 CA 2178914 A1 CA2178914 A1 CA 2178914A1 CA 002178914 A CA002178914 A CA 002178914A CA 2178914 A CA2178914 A CA 2178914A CA 2178914 A1 CA2178914 A1 CA 2178914A1
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- Prior art keywords
- group
- alkyl group
- substituted
- hydrogen atom
- represent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
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- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
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- C07C229/44—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by unsaturated carbon chains
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
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- C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
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- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
- C07C255/43—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms the carbon skeleton being further substituted by singly-bound oxygen atoms
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- C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/29—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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- C07C59/40—Unsaturated compounds
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- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
Abstract
A benzoylethylene derivative represented by general formula (I) and a salt thereof wherein R1 to R5 represent each hydrogen, -OR9 (R9 being hydrogen, C1C5 alkyl, etc.), etc.; R6 represents hydrogen, C1-C5 alkyl, etc.; R7 represents hydrogen, cyano, C1-C5 alkyl, -SOqR15 (q being 0, 1 or 2, and R15 being thienyl, phenyl, etc.), etc.; and R8 represents cyano, -CR22R23X (R22 and R23 being each hydrogen, C1-C5 alkyl, etc., and X being -NR24R25 (wherein R24 and R25 represent each C1-C5 alkyl, or R24 and R25 are combined together to represent alkylene, etc.)), etc. The derivative has potent activities of tyrosine kinase inhibition and cancer cell growth inhibition and is useful as a carcinostatic agent.
Description
~ 2178914 SPECIFICATION
BENZOYLETHYLENE DERIVATIVE
Technical Field This invention relates to a tyrosine kinase inhibitor, more specifically to a tyrosine kinase inhibitor containing a benzoylethylene derivative having specific structure or a pharmaceutically acceptable salt thereof as an active ingredient .
Background art In chemotherapy of cancer, many substances have been practically used as a medicine. In many cases, however, they are not necessarily in a satisfactory situation since not only the effect of the substance as a medicine is insufficient but also the inhibitory activity thereof is not limited only to cancer cells and the substance shows potent to2sicity so that side effects thereof are a great problem .
It has been known that a receptor of a growth factor con-trols function of differentiation and growth of cells and when a kind of aberration occurs, abnormal growth (excres-cence) and differentiation of cells occur and the cells become cancerous . It has been clarif ied that tyrosine kinase type acceptors participate particularly in formation of cancer, and found that these acceptors show peculiar tyrosine-spec~fic protein kinase ~tyrosine kinase) activi-ties and these activities are particularly accelerated in cancer cells (Cancer Research, ~L, 4430-4g35 (1991); Cancer Research, 52, 3636-3~gl (1992); Cancer Chemother. Pharma-col., 32, 1-19 (1993), etc~) . Based on these findings, it 217~914 .
has been already proposed that an agent which specifically i~hibits tyrosine kinase activity of a growth factor acceptor become to be a carcinostatic agent having novel function and mechanism with less side effect. In such a 5 material, there are, for example, microorganism-derived Erbstatin, Lavendustin, Herbimycin A, Genistein, etc., and as chemically synthesized products, benzylidene malonic nitrile derivative [~apanese Provisional Patent Publication No. 138238~1990; Journal of Medicinal :Chemistry, 32, 23a.4 (1989); Ditto, 34, 1896 (1991) ~ cyanocinnamide deriva-tive (Japanese Provisional Patent Publication No. 222153/
1988), 3,~-diisopropyl-~-hydroxystyrene derivative (Japanese Provisional Patent Publication No. 39522/1987), 3, 5-di-t-butyl-4-hydroxystyrene derivative (Japanese Provi-sional Patent Publication No. 39523/1987), Erbstatin derivative compound (Japanese Provisional Patent Publica-tion No. 277347/1987), and the like.
The conventional tyrosine kinase inhibitors are each insuf-20 ficient ' in their inhibitory activities and they are not yet sufflcient for using as a carcinostatic agent. An object of the present invention is to provide a novel compound useful as a carcinostatic agent which can be easily available, has high activity specifically as a tyrosine 25 kinase inhibitor of a growth factor acceptor, and thus has no side eff'ects' which are possessed by the conventional carcinostatic agents. Also, it has been well known that tyrosine-specific protein kinase (tyrosine kinase) has central function in differentiation and growth of cells or 30 in cell information transfer mechanism, and failure in control of tyrosine kinase activity in cells causes aber-ration in differentiation and growth mechanism of cells or in cell information transfer mechanism which is considered to directly participate in crisis of many diseases For 35 example, these diseases are arteriosclerosis (Am. J.
Physiol., 260 (4-part 1), C721-C730 (1991); Biochem.
BENZOYLETHYLENE DERIVATIVE
Technical Field This invention relates to a tyrosine kinase inhibitor, more specifically to a tyrosine kinase inhibitor containing a benzoylethylene derivative having specific structure or a pharmaceutically acceptable salt thereof as an active ingredient .
Background art In chemotherapy of cancer, many substances have been practically used as a medicine. In many cases, however, they are not necessarily in a satisfactory situation since not only the effect of the substance as a medicine is insufficient but also the inhibitory activity thereof is not limited only to cancer cells and the substance shows potent to2sicity so that side effects thereof are a great problem .
It has been known that a receptor of a growth factor con-trols function of differentiation and growth of cells and when a kind of aberration occurs, abnormal growth (excres-cence) and differentiation of cells occur and the cells become cancerous . It has been clarif ied that tyrosine kinase type acceptors participate particularly in formation of cancer, and found that these acceptors show peculiar tyrosine-spec~fic protein kinase ~tyrosine kinase) activi-ties and these activities are particularly accelerated in cancer cells (Cancer Research, ~L, 4430-4g35 (1991); Cancer Research, 52, 3636-3~gl (1992); Cancer Chemother. Pharma-col., 32, 1-19 (1993), etc~) . Based on these findings, it 217~914 .
has been already proposed that an agent which specifically i~hibits tyrosine kinase activity of a growth factor acceptor become to be a carcinostatic agent having novel function and mechanism with less side effect. In such a 5 material, there are, for example, microorganism-derived Erbstatin, Lavendustin, Herbimycin A, Genistein, etc., and as chemically synthesized products, benzylidene malonic nitrile derivative [~apanese Provisional Patent Publication No. 138238~1990; Journal of Medicinal :Chemistry, 32, 23a.4 (1989); Ditto, 34, 1896 (1991) ~ cyanocinnamide deriva-tive (Japanese Provisional Patent Publication No. 222153/
1988), 3,~-diisopropyl-~-hydroxystyrene derivative (Japanese Provisional Patent Publication No. 39522/1987), 3, 5-di-t-butyl-4-hydroxystyrene derivative (Japanese Provi-sional Patent Publication No. 39523/1987), Erbstatin derivative compound (Japanese Provisional Patent Publica-tion No. 277347/1987), and the like.
The conventional tyrosine kinase inhibitors are each insuf-20 ficient ' in their inhibitory activities and they are not yet sufflcient for using as a carcinostatic agent. An object of the present invention is to provide a novel compound useful as a carcinostatic agent which can be easily available, has high activity specifically as a tyrosine 25 kinase inhibitor of a growth factor acceptor, and thus has no side eff'ects' which are possessed by the conventional carcinostatic agents. Also, it has been well known that tyrosine-specific protein kinase (tyrosine kinase) has central function in differentiation and growth of cells or 30 in cell information transfer mechanism, and failure in control of tyrosine kinase activity in cells causes aber-ration in differentiation and growth mechanism of cells or in cell information transfer mechanism which is considered to directly participate in crisis of many diseases For 35 example, these diseases are arteriosclerosis (Am. J.
Physiol., 260 (4-part 1), C721-C730 (1991); Biochem.
2 1 7~q ~ 4 siophys. Res. ~::ommun., 1~ (3), I319-1326 (1993), etc.), platelet aggregation (FEBS Letters, ~ (1), 104-108 (1990); FEBS Letters, 309 (1), 10-14 (1992), etc. ), immune disorder (FEBS Letters, 27~ (2), 319-322 (1991); J.
Immunol., 1~ (9), 2965-2g71 (1991); Nature, ~, 253-255 (1992), etc.), inflammatiQn (Molecular Pharmacology, 37, 519-525 (1990); International Immunology, 4 (4), 447-453 (1992), etc. ) or the like. Thus, tyrosine kinase inhibitors are considered to be useful for treatment and 10 prevention of these -diseases.
Disclosure of the invention The present inventors have intensively studied to solve the 15 above problems ar,d as a result, they have :Eound that a benzoylethylene derivative with specific structure has potent tyrosine kinase inhibiting activity and cancer cell growth inhibiting activity nothing beyond this whereby they have accomplished the present invention. That is, the 20 summary of the present invention resides in a benzoylethyl-ene derivative represented by the following formula (I):
~ I
F~ ~ C O C :R ~ = C R ~ R
~3~
[wherein, in the above f ormula ( I ), Rl to F~5 each indepen-dently represent (1) a hydrogen atom, (2) -OR9 [wherein R9 30 represents a hydrogen atom or a C1-Cs alkyl group which may be substituted by a halogen atom or a phenyl group. ], (3) a halogen atom, (4) a Cl-Cs alkyl group which may be substi-tuted by a halogen atom, (5) -NR10~11 (wherein R10 and each independently represent a hydrogen atom, a phenyl 35 group, a C1-C5 alkyl group which may be substituted by a phenyl group, a benzoyl group or an acetyl group. ), (6) .
-SOpR12 (wherein p represenrcs 0, 1 or 2, and R12 represents a Cl-Cs alkyl group or a phenyl group. ), (7) a cyano group or (8) a nitro group, or~represent a Cl-C3 oxyalkylene group having 1 or 2 oxygen atoms by combining the adj acent substituents.
R6 and R7 each independently represent ~1) a hydrogen atom, (2) a cyano group, (3) a halogen atom, (4) a Cl-C5 alkyl group which may be substituted by a halogen atom, (5) -NR13R14 (wherein R13 and R14 each independently represent a hydrogen atom or a Cl-C5 alkyl group, or are combined together to form a C3-C6 alkylene group which may be inter-:
vened by -O- ) or (6) -SOC~R15 (wherein q represents 0, 1 or 2, and R15 represents a Cl-C5 alkyl group which may be substituted by a halogen atom, a thienyl group or a phenyl group which may be substituted by a halogen atom, a Cl-C5 alkyl group, a cyano group, a nitro group or a Cl-Cs alkoxy group. ) .
R8 represents (1) a cyano group, (2) -COR16 [wherein R16 represen~s a Cl-C5 alkoxy group which may be substi-tuted by a phenyl group, or -NR17R18 (wherein R17 and R18 each independently represent a hydrogen atom or a phenyl group which may be substituted by a halogen atom or a Cl-Cs alkyl group . ) ~ or (3 ) -CR22R23X {wherein R22 and R23 each independently represent a hydrogen atom or a Cl-Cs alkyl group, or are combined together to represent a C3-C6 alkyl-ene group which may be substituted by a Cl-C5 alkyl group, and x represents a hydroxyl group or -NR24R25 [wherein R24 and R25 each independently represent ~a) a hydrogen atom, (b) a phenyl group which may be substituted by a halogen atom or a~Cl-Cs alkyl group, (c) a Cl-Cs alkyl group which may be substituted by a phenyl group or a Cl-Cs alkylamino group, (d) a C3-C8 cycloalkyl group or- (e) -COR26 (wherein R26 represents a Cl-C5 alkyl group, a phenyl group or a Cl-Cs alkoxy group which may be substituted by a phenyl group 1, or are c~ombined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27--2 ~
(wherein 3~27 represents a hydrogen atom or a C1-Cs alkyl group. ), or a C3-C6 alkylene group which may be substituted by a C1-Cs alkyl group. ~ . ~ . Provided that when R6 and R7 represent hydrogen atoms simultaneously, R16 does not 5 represent _l~gl7R18 ~
or a salt thereof, or a tyrosine kinase inhibitor contain-ing the above benzoylethylene derivative or a salt thereof as an active ingredient.
10 In the :Eollowing, the present invention is; explained in detail The tyroslne kinase inhibitor of the present invention contains the benzoylethylene der_vative represented by the 15 above formula (I1 or a pharmaceutically acceptable salt thereof as an active ingredient. A5 the halogen atom defined in the formula (I), there may be mentioned, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., as the C1-Cs alkyl group, there may be men-20 tioned a methyl group, an ethyi group, a n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a neopentyl group, etc., and as the C1-C5 alkoxy group, there may be mentioned a methoxy group, an ethoxy group, a n-25 propoxy group, an iso-propoxy group, a n-butoxy group, an iso-butoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentyloxy group, a neopentyloxy group, etc As the C3-Cg cycloalkyl group, there may be mentioned a 30 cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group, and as the C1-Cs alkylamino group, there may be mentioned a methylamino group, an ethylamino group, a n-propylamino group, an iso-propylamino group, a n-butylamino 35 group, a tert-butylamino group, a n-pentylamino group, e~c.
2~7~4 As the Cl-C3 oxyalkylene group having 1 or 2 oxygen atoms, there may be mentioned -ocH2cH2-l -cH2ocH2-~ -CH2CH2O-, -OCH2O-, -OCH2CH2O-, etc., and as the C3-C6 alkylene group, t~lere may be mentioned -cH2cH2cH2-~ -cH2cH2cH2cH2 -CH2CH2CH2CH2CH2- and -cH2cH2cH2cH2cH2cH2-~
Among the compounds repre~ented by the above f ormula ( I ), preferred are compounds in which R8 is a cyano group or -CR22R23X {wherein R22 and R23 each independently represent 10 a hydrogen atom or a C1-Cs alkyl group, or are combined together to represent a C3-C6 alkylene group which may be substituted by a C1-Cs alkyl group, and X represents a hydroxyl group or -NR24R25 [wherein R24 and R25 each independently represent (a) a hydrogen atom, (b) a phenyl lS group which may be substituted by a halogen atom or a C1-Cs alkyl group' (c) a C1-Cs alkyl group which may be substituted by a phenyl group or a Cl-Cs alkylamino group, (d) a C3-Cg cycloalkyl group or (e) -COR26 (wherein R26 represents a Cl-Cs alkyl group, a phenyl group or a Cl-Cs 20 alkoxy group which may be substituted by a phenyl group. ), or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27- (wherein R27 represents a hydrogen atom or a C1-C5 alkyl group. ), or a C3-C6 alkyIene group which may be substituted by a Cl-Cs 25 alkyl group. ] . } . More preferred are compounds in which R7 is a hydrogen atom, a cyano group, a Cl-C5 alkyl group or -SOclRlS (wherein q represents 0, 1 or 2, and R1S represents a C1-C5 alkenyl group which may be substituted by a halogen atom, a thienyl group or a phenyl group which may be 30 substituted by a halogen atom, a C1-C5 alkyl group, a cyano group, a nitro group or a C1-C5 alkoxy group. ), and R8 is a cyano group or -CR22R23X {wherein R22 and R23 each independ-ently represent a hydrogen atom or a Cl-C5 alkyl group, or are combined together to represent a C3-C6 alkylene group 35 which may be substituted by a C1-C5 alkyl group, and X
repr-esents a hydroxyl group or -NR24R2S [wherein R24 and R25 2~789~
each independently represent (a) a hydrogen atom, (b~ a phenyl group which may be s~ubstituted by a halogen atom or a Cl-Cs alkyl group, ~c) a C1-Cs alkyl group which may be substituted by a phenyl group or a Cl-Cs alkylamino group, ~d) a C3-C8 cycloalkyl group or ~e) -CORZ6 ~wherein R26 represents a Cl-Cs alkyl group, a phenyl group or a C1-C5 alkoxy group which may be substituted by a phenyl group ), or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR21- ~wherein R27 Le~L~L~ ts a hydrogen atom or a Cl-Cs alkyl group. ), or a C3-C6 alkylene group which may be substituted by a Cl-C5 alkyl group. ] } .
Further, as a particularly preferred compound, there may be men~ioned compounds in which R1 and R5 are hydrogen atoms, R2, R3 and R4 each independently are a hydrogen atom or -OR9 (wherein R9 represents a Cl-Cs alkyl group. ), or R2 and R3 are combined to be Cl-C3 oxyalkylene having 1 or 2 oxygen atoms, R6 is a hydrogen atom or a C1-Cs alkyl group, 2D R7 is a hydrogen atom, a cyano ~roup, a C1-C5 alkyl group or ~SOq~R15 (wherein q~ ~L~ ts 2, and R15 represents a thienyl group or a phenyl group which may be substituted by a C1-C5 alkyl group or a nitro group. ), and R8 is a cyano group or -CR22 R23 X~ {wherein R22 and R23 each independ-ently represent a hydrogen atom or a Cl-C5 alkyl group, and x~ represents -NR24'R25' (wherein R24' and R25' each independently represent a C1-Cs alkyl group or are combined together to represent a c3-C6 alkylene group which may be substituted by a C1-Cs alkyl group. ) . ~ . Among them, more 3 0 preferred are compounds in which R1, R4 and RS are hydrogen atoms, R2 and R3 each independently are -OR9 (wherein R9 represents a C1-C5 alkyl group; ), R6 is a hydrogen atom, R7 is -~Oq ~ R15 ~wherein ~ ' represents 2 ~ _and R1S represents a phenyl group which may be substituted by a C1-Cs alkyl group or~ a nitro group. ), and R8 is -CR22 R23 X~ {wherein R22 and R23 each independently represent a C1-C5 alkyl ? ~ 7 ~
group, and X~ represents -NR24"R25" (wherein R24" and R25"
each independently represent a C1-Cs alkyl group. ) . } .
As the rLost preferred compound, there may be mentioned 5 compounds in which R1, R4 and R5 are hydrQgen atoms, R2 and R3 are methoxy groups, R6 is a hydrogen atom, R7 is a phenyl s ul f onyl gr oup, and R8 i s - C ( C~13 ) 2N ( C2Hs ) 2 -As a salt which can be formed by the benzoylethylene 10 derivative represented by the above formula (I), there maybe mentioned, for example, inorganic acid salts such as carbonate, bicarbonate, hydrochloride, sulfate, phosphate, etc., or salts of organic aclds such as formate, propionate, oxalate, fumarate, maleate, citrate, tartrate, 15 benzoate, phthalate, methanesulfonate, 4-toluenesulfonate, etc., and the like.
Further, the present compound can also form a hydrate.
20 In the following, preferred specific examples of the compound of the present invention are shown in Table-1.
R~ R C ~ CR~ = CF~7 R8 R~ s ~ ( I ) 217~914 g able-l ~1 0 ~\ ~ (R7)=C (2~ o Z3 1 ~ Rs Co;~-~urd R 1 ~ 7 2 3 R ~ R 7 ~o, =
H H H H H 'I H C,' r~ H H H H H H 1~ C0~7J~e 3 ~ H H H H H rl CO73u _ _ . _ . _ }il H H H H H H CO7BI~.
1-~ 2 ~e ~ ~ H H C.~l :~ H OH C.~l H -~i H H C~.' H OH H H H H c-r~
3 il H 03n H H H H C~
9 H H 0i1' H H ;l H C,.
10 H ~'e OH H H H H C.
1 I f~' .H C I H H H H C;~
17 H Cl Cl H H H H Cr' 13 H O.}!e Or.~ Cl i, H H C~
1~ H 0~2 OU2 B- ,! H H C~
1~ H O~!e Or.~e C~ H H ii CN
16 H ~le G~e NO2 H H 1I C~i 17 H 0'1 OH ~i ~02 I: H C~i -2 ~ 7~ 4 able-l (conLd) orl- 2- 23 R~ D~i ~ô 2 .
la H ~le ~H ~e H H H C."
19 H ~[e Q~e ~e .Y H li 5,~l ~0 H ~le O~fe e H H H CO-,~!e 7 I H ".e ~ le H H H 50~ 'e H 3 5H }~ H 'Ll H ca- ~
73 3 OH 51i H 1~ H r CO 4 D3(e OH H H H H CO.-,Ye 75 ~ 'e O~n .~ H H H CO-,~I~
76.~ e D~e ~ H H X CO.,~e 77 U ~ 0~'~ C I 11 7rt H ca-~e 23 ~- 04~e Q re 3r H H H CD~e ~ H H Q3~e H H P R CO.~e 30 H --D5~70-- X H 11 Ir; CO~. e 31 H H -l~e2 H H e H ~C~e 37IY H -~l2 H H .~' H CO~e 33 h H S~e H H H H C02~e 3~ H DUe O~le C~ rl h H ~5-,~e 35,~ We QYe CFS H ~ H U1~'1e 36 ~ O~e O.''e CFS NO~ H ~I CO~'e .
37.~ O~e O!le NO2 r' 'i H CD^,l!e 3a H C~e Q!le ~0~ rl Ca ~L!e ~ ~ 7~
Tabl~-l (contd) com- R ' ~2 R3 ~ ~ R-- 7 6 ~ 8 N~ . .. ..
3S H 5f~e Cl H H 'r' H C0-,.~fe ~0 il Cl G~ H fi H h CO,~fe 1li C I C ! C I rf H H CO-,~fz ~ ~ ~I C I Ol~e C ~ H H H CO ,l~e d3 R 5l O.~i Ci It ~I X CO ,~.e h' ~e OH l{e H H H CO~,e S h l!.e O~ e ~i~e H h' H CO~d-e .
fi' ~i'e Of~fe ~e H H H CO7nSu ~7 H O~le O~e ~le H H H CO~Su 8 H H OH ~e H H H W7n3u ~9 H H Olfe f~.'e H H h C0~;~3u , ~0 L; h C! ~fe H H H W7r'~u S! H OH OH ~fe H H H W7nSu ~2 ~1 01`~ OH .'.fe H 1~ H C07S r 53 li OlJr OH ~.e H H H CO~
H O.~fe Oen rlf2 H H H C023r ~5 H H 03n l.fe h H h' Cf~-,3r ;3~ H H O~le .~e 'l H h C073r 57 I H C I .~le H 11 H co7e ~
58 H Cl Cl ~e '.~ C07hr ~9 r' C ~ C I 'I H ~ C07~ r 2i78~4 Ta~ 1 (contd~
poLlmnd R ~ 3 R ~ ; R i' .~ 7 r~
NO .
6~ ~. C I r e C I ~{ X H C023r 6I R L~fe D~e h H H H ~ i.'f~
67 L f1 Q~le ,L ,L, R H ~ 2 ~i3 h i C~ H IL.' H H ~ ,?~ff7 H H 03n H LLI ~ '~f < "~H7 6âh' OH OH H H Ll H ~ f:fH7 6~ .H OH L~H H L' X H ~,~i~f~e Dt H G~e O'f ~f 'rf H H ~h'^' 60 ~ H H H H L! 5~h~e 6g H L; ~le H ~f H H 5 ~iY,~'e îO L ~ Cl H H H H 5~?f.L~fe 7I R H ~3n H H E~' H ~,~
77 ~ H D3n h H H H ~`f~L2 t3 If ~l a~e H H H H ,~ ?fE t2 H O~e D~e H H H H ~ ?fE t 2 7:~ H ~.!e 03n H H H H ~,~iEt2 ~ -- .
t6 H ~, OH H H H H ~ ~ L 2 ~t II '~ Orf H H H ~f ~/ ~IEt~
î 8 ,( H C I ~f H H H ~ f~E ~ 2 tg H Cl Cl H ~l ,f H , I-~Fl~
30 ~; C ! ~!4e C l H H H ~ N~ L 2 23789~
Table-1 ( contd) Co~n- Rl R7 R3 R~ R~ R6 ~7 R8 No .
. .... .
8I IH' O~!e 0Ue C! H H H ~N~I~
., 82 8 0.U_ ~e CP3 8 H H ~i~
83 H Dlle D~e ~e i.~ H H ,.
B~ h' O~e ''~e S~fe H H H ,N' Pr~
8~; H 0~e ~.Ze CF3 H H H ~,ii! Pr 7 8b H ~ie 13Ue H l~ H H ,tZiPr7 &~ H H We H ~ ~, H ~,~ii Pr2 88 H H ~3n I~ H H H ~,ii! ?r 7 H H Cl ~ H H H ~Pr5 90 H H H .~ H H H ,;liiPr7 91 H O~'e 5~3n H H H H ~ pr7 57 H 011e 5~ H H H H ~C~?~ip~7 93 H O~e OH Cl H H R ,~hi?r7 9~. pl O~e ~H C I ~{ H H ~ N~>
9a H Oil.e 0' 'e C I H H H
96 H ~ O~e ? r H H H
97 H O~'e O~le H H .'i H
98 H H 0!~'e H H H H >~ 'I,~) g3 H H C I H H H ~l >~ li--) 7 ~I H Y H ~ N~
IOL H H O~n H H ,~
-217~14 Ta~le-1 (contd) - , r ~ _ C:om- R! R2 7~.f R-i ~ S RS R~ Rc No !0~ 3 H H h H y .
lD3 Ll D! H Cl H h' H >C~ li~
lOi :1l H ~ H H X H >C~ ~i'7 lD~ ;l H Slle H h X H ~
106 p; lu -Nl'~2 H H X H ~ ~if~) 11)~ ,{ -OCI;lsO~ H H H H ~ ~f~--) 138 H H ~ ~F2 H H H X
109 ~ O~i~ Ol~h~2 H H h' H
-~ 7 110 H OL~ O~e 1l H 1 H I ~
~t~
111 H H G~e H H H H \l--die , ~12 H GH 0!~ H ~ ~ H I ~
~-_;7 3 H H Cl H H H ~e ~N~[7 I! ' H H H ~ H Hl h .
H H rl ~1 ' I H' X ~ ; 7 ~ 217~914 Table-l ( corLtd~
com- R l ~12 F~ 3 ~ 6 ~ ~ R
No . _ .
1'~6 }! h Ohe t; H x~ z 111 ~ Dl~- Oble h H 1~ tl X~~2 113 H D~le 53n H H h' X~ç~2 ~#ET 2 11 H Dh'e D~n H H H H /~
~.~
1?0 h' D.''e nJ~le H H H H
~E.7 1~1 H 1:1 ~e H H H H ><
~C~7 !?7 H H ~! IA H H H
. . . .
~ 2 173 .; h H H H H
~ ~2 12A H DH OH H H H H /~
125 H OH D,l H H
!76 :i We 011 ~ I h' --217891~
Table-1 ~co~td~
com-p~ D~} R7 R3 R4 D-, R ~ / R3 No .
. . .
~2t~
L~7 t. ~ke G~2 ~ H ~, H
~13 t ~1 1~3 H H Lf2 h H H H ~Xr ~E
179 h t~ C 1 H t H H ~><r !3~ H H C I H H H ' ~
131 H R Oif2 H H H H \, N~>
= .
137 H D.~e D.L'e H H H H >~
133 H L4~ 0~-12 H H H H ~>
I ~ H O~'e G~!2 C I H H H \~ ~
.
H Dl~2 C~e ~ r tt 1I H >~
~6 n 0.4e O~!e Ct'3 H H H
~ ~ ~ 7~
~able-1.. (cont~d com-~nd p~ 2 R3 2~ ~s ~ R~ 28 No .
137 H ~e 53~e S02Ue ~ H H ~N~>
138 H 0~e ~le ~e H H H >~
l~g H O~e {dfe ~'Oq ~ H H
11 0 ' ' C~ 4e H NO 2 H ~ ~N~>
. .
OH aH H H H ~ ~N~>
1-7 H H O~ H H H X ~) H ~3~n H H H h' lAA ~ H H H H H H >~
H-OCHza- H ~I H ~[
1 A 9 H C; G~ C I ~i H ~ ?
2~89~
able-l ~ contd) Co~
d R ! 2 ~ p~ 3 R ~ 7 ~ 8 No .
Cl i~ Cl h H H
e _~ H Cl !l Cl H H ~ O
.YE
1~9 H -H 13~ C! H H H ~S
:~0 .'J H ~'e H H h' \,.i~Et2 ~,~I,-t2 a~lD O~le h H ~ H ~
'~12 1~2 H Qljo OH H H H H ~j 1:53 ,:f H OH .~ H H ~Y
~?lf~t,, 15~ ,~ H Cl H H H H O
~N~t2 155 H H rl .~ H H H
156 H ~' H H 1,' H 'I ~N~
~1~8~4 Ta~le-1 ~co~td) -c~)m-pOUD~ ~I B~ R3 R4 Rs R R~ R~
N
157 il H O:~e H H ;,! h' 1~8 H ~e Dile H H H 1' ~;
1~ H ~le 03n i~ H h' '1 1~0 '' H Cl H H ;~ H
161 H H 03n ~ h H H
h' -DCH20- H h H H
16a H -D~P.20- H H 'H H
16' H C.e O~e H ,~ H ~,~
16~ H OH OH H H h H ~ r~>
!65 H H OH h t! H tl ~
2 1 7~9 3 ~
Table-l ~ co~t~L) com- e1 ?- ~3 R 1 ?~ ~ R-o F~ 8 ~lo .
rl C I H H H H ~N~>
168 '~ R 1~ i{ h ~{ H
, ~
Ir~3 ff ~ H H h' li H ~5 2 ~ ~EL7 170 'r; H O~!e ~ H
171 ~ O~e 1~ R H H l, ~2 77 Irl [~J'e 0~ H h H ~ EL2 t 7 173 H H DB~ H H ~ 3 2~
,~ {IE t 7 lîg ~ H Cl H H H H 2S
!7~ h' H Cl ~ H H H ~E~2 176 H H G~e ~ rl ~ ~flE~2 . .
21f89~4 Ta~le- 1 ( contd) com- E' R7 ~ R' R~ , E~ ?~a .
177 H O.!e Q~.e H i1 H H
~3L~
5 Off Of~ H r! H H ~
79 H H OH H H f' ~5 L2 ~ f~E~2 H H H H H :~ ff 181 H H H H f5 CY H C~
1~ :Y iY D~le H .Y C~ H CN
H ~e O.~le H H CN ~5 CU
1~ H OH OH H H C,Y H C~
If3;S H H H H fl C~Y ;H Ct5 106 H H 05~il H H CN H CN
8 I H H C I H H C,V H C~l ~8 H H C I H H SO2Ph H C[Y
1a9 H H 0.5.~e H H SO~Ph H C;~
!90 .~ G~e Ol,le i'. H SO2Ph , C, 191 H O~Ue OH ~I H SO7Ph H C~
19~ f5' G5~e o5~n H H SO7Ph H C~', !93 H ~,5~e O'~e H n S?n H C,~l ~ 2~7~9~
Tabl e-l ( c~ntd) c ~ 2 R3 p~ p~; p~ ~7 R~
NO
19~ ~' Ol~e Qlfe H H Cr ~ R C~
lSa j1' G~le O~e { '~ ~F3 ~ CN
1~ H Ole Q~e H H SOPh H C.~l 197 11 l~ Q~le R H SOPh H C}i lS8 H H ~Xle .H' H SOPh R GO2~e 199 H ~e OL(e H R SO~h H ~e 2Do :~ Q'~ QH H H SO~.~ H C02~e 201 i~ H OH n 1~' SOPr H CQ2;~e 207 H L71l2 O~e !1 H ~ ~' CG2 ~e 203 H R .1 R H ~(e H CQ~L'e . _ ... .
70~ R~ i~,! ~e H H SO2Ph H CO~lle 2~5 H C~!e D~!e H H SPh H CG2Lfe 2~S H Ol-le G.L~e H h SQ~e H CQ~Le 701 H H C l H H S02~e ~ CO2"e 20S H ~: C I H }~! SO211e H CO~Bn 209 H H Q~e '~ H S02Ye H C023n 210 h D~e Q~e H H 502P~. H CO28~
211 'I G~le We H H .~le H -CO'~ Ph Z12 H 'I ~I H H '!e ~ -CQ~ Ph 2!~ H H C I H H ~le ~l -CO~ iPn ~ .
? 1 7~891~
Table-1 (contd) com-Rl RZ ~3 R4 Rs R6 R~ R
No .
.
2!~ H H C! Y' H CN H -COr3H~CI
, 7!~ H ~!r Dile H ,~ CN H -CD~.~Cl ~16 H ~le O~'e H H C,Y H ~
. . , ~1 ~17 H G~'e Oble ~ H CN H -WYH~
71g ~ le O~!e H H ' -N~ -CG.i~Y:'h .
71S H ~'e ~e 1~' h' '`O~'e H -æ~ H O~le O~le h' H SO2Ph H -~HP~
771 Y H ~le H H S~2Ph H -C~-X?
777 H H C l H H S[32Ph H -CG~Ph ~3 H -~H~CHz- H H S02Ph h -C~ iHPh 2~ H D~le C~[e H H H SPh -CO'i~Ph 7?5 H Ql~e D~!e H H H H ~I~P~2 776 H D~'e 5~(e H H C,l ~ t 7~7 H fl O.''e H H C.'~ rl ~ ~ ~ 2 ~2a H ~i C ! H rl C~ H ~ ~ 2 . .
2 1 789 ~ 4 Ta3~le-1 (contd) _ _ .
com- I ~ 2 R ~ R 4 ~ 7 p~ 8 No .
~2~ H H OgD -il H CY ` ti~2 230 H H D3n ~ ~ Sû7Pn H ~t2 ~31 H ~e l~le H H SD-~Ph H ~~.~t2 a~'e al~!e H H SD~le H ~t2 ~33 H Q~le ~le H H SQ2CF3 H 5~i~1~.2 234 ~ e ~lo H H S02CF3 H
~35 H ~.;e O.,le H H Sa~h H r~3 ~3~ H H aLf.e H H SD2Ph H ~ N~--) 731 H H Cl H H S02Pnh H N~>
738 'H H H H H SO~Pb H
~39 H D~e ~1~ l~ H C~l H .i'~>
~0 H H Q~e H H CN H i{--) ~! H H ~gn H H C~i H '~
7 " H ~gr~ H H SOPh H
~3 H H ~e H H SO?h 7~ H O.i[e O~!e H l! SOPh H ~ r,'~
r1~t 2 245 H O~e Ol.l:e H H SOPh H X
' ~t ~!6 H Ol'e We 1~ ~I CN 2 2 1 7~9 ~ ~
~able-1 (Co Com- ~I R7 ~:~ P`~ ~5 R6 a7 R~
N~
l, H Qi.fe H H ~ ?3. L7 ~8 H H ~ C~ L, ~9 ~1 H I~Dn H k C^. ' r3! ~A 7 _~ ~t~
~50 H H 53 n 3~ H SOFI~ H
~t~
2 I H H SOPD H ~ A
'i H ~ e H H C~3Ph c ~3~ t 7 ~3 H H H H H ~e ~12 -Ca~lPh --~ 7 H ~e ~le H H 50733~ H X
H H 01~e H H Sa73.'h ,\ .~nL 7 . f~ h~
~6 H -~CH~?O- H H Sl37Ph H >
_ _~ t~l3, L
~57 H ~ C I 'I 'I SO7Ph H A
2~8ql~
T2ble-l (co~td) com- Rl R~ R~ R- R~; ~ô R~ R~
No .
2a3 .HI li H H H 507?h H f->~ t 7 2a~ H ~ H H St~_h h ~><
2EO H O?le Qlle H H 507"e ~ t 7 201 H H 0~2 H H ~O,Ye H ~i ~S2 H H O.~'e ~ H
~63 H O~!e ~ e h H ~;e J~ R
2~ H Q~ DH !,, H Ue ,>~h3 t .
26~ H IY OH H H ~e H S<
266 H ~[ Qs~ H H ~t H J><
2~7 H ~.~le O.Ye '~ H Et ~l _'~i~'Et2 217~14 T2~ble-1 ( cr~ntr~
COL~_ R 1 R 2 R 3 R ~ R :' R ~ R ~ R o NO .
2~8 H G31e O~e H H SDn H ~< -2D~ Ir 0~1~2 O~e 1~ h' H 53h '~< 2 .
' ~E7 ~:~0 H H 03~ H H H ~i~h '><
~ ~t~ I
~71 H q O?r!e H H H S4'2 ~\~ 2 ~L7 ~7~ H a~2 0~'2 H H H ~{e ~<
. =
273 H O?IE G~- H H H S~:elie ~ t 2 = =
H H G~le H ~ H S~2~e ~ 2 - ~t2 ~75 H H C I H H H S02ilz ~><
t ~76 H H h H ~ q S~2Y2 '\~<
f~ ~iE;t2 2T7 ~,' H H r( ~ I SO2P~ ~
2 1 ~
Table-1 ( contd) Com- Rl ~7 R3 R' Rs R~ R~ R-No .
~iEI 2 273 ~ Olle al~e H H H SO2Ph '><
~7a H y n~e H ~I H ~O~Ph ~<
- h~7 730 H H DBr~ H H H ~O~Ph X
2~1 H H Cl H H H S07Ph ~/\~ 2 737 b Cl Olle C~ H H SO2P}l ~'\/ 7 si~t 2 ~83 H O~e O~e C I H H sa2P~ ~\~
_,~ h~7t 7 2~4 H D~[e D~le Br H k ~`07Ph X
t 7 HQ:~e a~e cr 3 I H S07Ph X
2;~6 H O~e O~e N02 H H f~E.z 2~7 H a.'~ Je H tl ~ t 2 2 ~ 7~91 ~
~a~le-1 ( ccmtd~
com- Rl R2 R ' R- R~ R'3 F~7 R3 ~io .
OCH7Q- H H H 502P'~
~9 H --DC~zO - H ~0 2 ~ 5~2Ph ~< N~
790 H --O~H20- O'~e h' H S''.,Ph ,5<N~
29i H O?~e G~!e O~e H H S02r;~
2~2 H C I C I H H H SG-,Ph 29.~ le O~le H H -H SO2~4c '\~
29- H ~e OJ,.~ H H H SG2~ C I ~
~95 H OLle Ol~!e H H H 503h ~?~ 2 9~ H 0~1 G~!e H ~I CP 3 SOD~ ?E 2 ~ tiE L
297 H Olle O!le H H ~ CP3 X
79~ ~, OlJe OU~ H H H P ~E~2 2 ~ 7S~,9 ~ 4 Ta}~le-1 ~contdl p~ ~ I R7 R~ R~ R~ ~ R ~ ~c No .
æ~s x D~le ~{2 'H H H SD~,Ph ~/ #~>
3DO H H Olle H X H S02Ph ~/~
3~1 H ~ C 1- ~I H H SO zPh 30~ H H 0~ H H H SO7Ph x~
303 H H 03n H H ~ie SG?Pn 3C~ H 031e ~le H H C" 53~Pn ~,~
3a5 H ~e ~e H H SOPh SO7PI' ~ 'i~) 3~S H Q~l= O"e H H 53~Ph 507Ph ~/ '~
307 H Ol~e Q~e H H SO-~le SO7Ph ~/'~
3~8 H O.',!e Dl~e 'I ~ SO7~e SO 7~Ue ~/ rl;O
-9~4 ~a~le-1 (contd) com- R7 R3 R~ R~; R2 ~ ' R~3 No .
309 H D~e ~e o h' H S0 ~f6 ,< ~
310 X OHe D e H ll CN So~ e~5~t~) 3l1 H a~l0 ~e ' H ble S0 ~-~e 31~ N &,~e D~le H H H SO~,3 313 .~ a3l ~le h H H Sû~e 314 H Oh'2 D~e H H H S~-'le ~N~
315 H H ~e H H H SO-,~e ~/ ~`'~
3!6 H H Cl H H SD7~!e 3!7 H H C l H H H C~
318 H OVa O~le ~ H I C~
2~7~91~
Table-1 (coIltd) com-polh~d R ! R~ ~3 R~ R~ P~ R7 R~
~o 31S 11 Q~e Odle H H H r ~S<~
3~û H ~!e OYe H H H Sl~3 ,<r.~) 371 H H O~(e H H H S~:e ~27 H H Cl ~ H H SPl ~5<h'~
~3 H H Cl H ~ H SPh ~
32~ b H Ot~l_ H H H SPr ~.ri~) ~75 H H Qqe H H SOPn H
326 H H OYe H H âOl'h H ~S<`
327 H OY.e C~fe H H H âO2Ph ~t~
~28 H ~t!e rl~e t( H t~ â~Ph 'S< ?lH2 217~ql~
~able- 1 ( corl td ) . ~ ~ .
pOU~ p ! R7 p~3 p~ ~ R6 ~ R8 NO .
3~5 H GMe ~ H H H SPh ~iliPr7 330 H H JMe H ~I H SPh ~,~lip{7 331 H H C~ H H H SFh ~ r7 33~ H H Cl H H H SGPh ~,.~i?r2 333 .~ H D?~e ~ H H SOPh ~I~!pr7 33~ H Q~le ~'.~ H H H SOP~I ~, NiP~ 7 33~ H ~!2 0~(e H H H SO7Ph ~ Pr~
336 H H f.~e H ~ H S02PA ~3Pr2 337 H H Cl ï r H S02Ph ~lip,7 338 ~I H Cl ~ H C;~ H ~ NiPf7 2 ~ ~$~ 1~
3a, Table-1 ( corLtd) co - R " ~ 3 ~ 4 R ~ ; 8 No .
33g X C~'.{e O~le h' H CN H ~iPr, 34D H ~e O~e ~I H CN H ~,iliPr2 3~1 H DUe O~e H H 502Ph H ~,NiPr2 .
34~ H O.;~e Q~ H ~!e H --,ip 3~3 H O~e ~e H h' H .U~ ip}2 3A~A H O~e ~e H H H 1~ ~13h~Ph 34:~ H H H H H H ~:e i~0.~3Ph 346 H H H H H 11 ~le CO~e N~
3A7 H 0!~ ~Ye H H H -h'~:~Ae 342 ~i Ollc O~le ~I r( H - ~
2~7~
Table-1 (co~td) com- R~ R~ R R~ R8 No .
3~3 H OUe O~te H H H Cii ~,/Nr~l2 3a~ H. OUe O~le H H H 50 ~10 ~< U~ t _ _ 351 H ~:[ il~^ i{ IH H -SOA~ille ~
. 357 H 0,!l2 a~l2 H u I -S~~~ ,5<N~-2 The compound of the present invention represented by the above fo~mula (I) can be prepared through, for exa}3ple, the following route.
20 1 ) H~ R8~
R I ~l R ! OIH
p 2 ~ C~:10 U----R 3 (r~/ ) R2~ --t ~ ~ Al=L i ~ ~(g ~ = R 4 h~logen CtO.~. .la ( V ) tl C;~
R I 0 or RSH
a 3~ o r ~ S 2 tl R ~ la. k, Cu.
P~2A t (p~=~lkyl) ( lTr ) 3 5 ( Scheme 1 ) 27 7~q~4 ~wherein R1, R2, R3, R4, RS and R8 are as already defined. ) For example, by reacting the metal acetylide represented by the formula (IV) which can be prepared by making a base of 5 an organometallic compound such as butyl lithium, ethyl magnesium bromide, etc., a metal alcoholate such as sodium methoxid~ etc., a metal hydride such as sodium hydride, potassium hydride, etc. or the like act on the acetylene derivative represented by the above fDrmula (III) in a 10 suitable solvent including an ether such as tetrahydro-furan, diethyl ether, etc., a hydrocarbon such as benzene, toluene, etc ., a protonic polar solvent such as methanol , ethanol , etc ., an aprotic polar solvent such as dimet~yl-sulfoxider dimethylformamide, etc. or the like at a temper-ature of -100 C to +100 C for 5 m~nutes to 12 hours, with the benzaldehyde derivative represented by the formula (II) at a temperature Df -100 C to +100 C, preferably at a temperature of -30 C to ~50 C for 5 minutes to 24 hours, pref erably f or 3 0 minutes to 12 hours, the adduct repre-20 sentea by the formula (V) can be prepared. sy oxidizing the compound (V) in a suitable solvent, fQr example, in a hydrocarbon such as benzene, toluene, etc., in a polar solvent such as acetone, wacer, etc., in a halogenated hydrocarbon such as dichloromethane, chloroform, etc. or 25 the like, the compound of the formula (I) can be prepared As an oxidizer, there may be mentioned, for example, a metal oxidizer such as manganese dioxide, chromic acid, etc., and an organic oxidizer such as oxalyl chloride-trifluoroacetic acid anhydride, etc. Further, for example, 30 by subjecting the compound (V) to a hydrogen transfer reactiDn using aluminum isopropoxide or zirconium chloride in a carbonyl compound such as acetone, cyclohexane, etc., the compound (VI) can be also prepared.
2 ~ 789 ~ 4 Rl Rl R 2~ C O? ~ R ~ C 0 X ( VI ) 5 R4 R4 (1¢), P~(O}.C~
(~) (~) ( Scheme 2 ) (wherein R1, R2, R3, R4 and R5 are as already defined, ) Further, for example, as shown in the above Scheme 2, by reacting the acid halide compound (VIII) obtained by reacting the benzoic acid derivative represented by the 15 formula (VII) with thionyl chloride, phosphorus penta-chloride or the like in a hydrocarbon type solvent such as benzene, toluene, etc. or a halogenated hydrocarbon such as dichloromethane, chloroform, etc., with the compound (IV) in an ether such as tetrahydrofuran, diethyl ether, etc., a 20 hydroGarbon such as benzene, toluene, etc. or a mixed solvent thereof at a temperature of -100 C to +100 C for 5 minutes to 24 hours, the compound (VI ) can be prepared .
Further, for example, by reacting the compound (VIII) with the compound (III) in the presence of catalystic amounts o~
25 a palladium complex and a copper (I) compound in a suitable solvent such as tetrahydrofuran, benzene, etc. at a temper-ature of +10 C to +100 C for 30 minutes to 48 hours, the compound (VI) can be prepared.
30 By reacting the compound (VI) with a 0.5 to 10 e~[uivalent amount of a metal cyanide such as sodium cyanide, potassium cyanide, copper (I) cyanide, dialkyl aluminum cyanide, etc.
in an alcohol such as ethanol, etc., a hydrocarbon such as hexane, toluene, etc., an ether such as diethyl ether, 35 tetrahydrofuran, etc., a polar solvent such as acetone, water, etc. or a mixed solvent thereof at -70 C to +200 C
.
for 0 5 to 48 hours, a compound in which R6 or R7 is repre-sented by CN among the compounds of (I ) can be prepared .
Further, for example, by reacting the compound (VI) with an 5 amine represented by the following formula (IX):
HNR13R14 (IX) (wherein R13 and R14 are as defined in the formula (I) ) 10 in a polar solvent such as water, methanol, ethanol, etc., in a suitable solvent such as benzene, acetone, dimethyl-sulfoxide, etc. or in a mixed solvent thereof at 0 C to 150 -C for 5 minutes to 48 hours, a compound in which R6 or R7 is represented by -NR13R14 (wherein~ R13 and R14 are as 15 already defined) among the compounds of the formula (I) can be prepared.
Further, for e~ample, when the compound (VI) is reacted with a sulfur-containing compound represented by the 20 following formula (X~ or (XI):
RlSSH (X) R1SSO2H (XI) 25 (wherein R15 is as defined in the formula (I) ) in a suitable solvent such as water, ethanol, benzene, acetone, dimethylsulfoxide, etc. at -20 C to 150 C, a compound of the formula (I) in which R6 or R7 is repre-sented by SOlR15 (wherein l represents 0 or 2, and R15 is 30 as defined in the formula (I) ) can be prepared. In place of the compound represented by the formula (XI), a salt such as correspol'iding sodium salt, lithium salt or the like may be used depending on stability thereof, or the reaction may be carried out while generating the compound (XI) in 35 the reac~ion system by adding an ec~u~v-alent amount of 2n acid such as acetic acid, hydrochloric acid, etc. to the sal t ? ~ ~7~ f ~
sy reacting a compound of the formula (I) in which R6 or R7 is represented by SR15 (wherein R15 is as defined in the above formula (I) ) with an inorganic oxidizer such as chromic acid, selenium dioxide, sodium metaperiodate, etc., 5 a peracid such as m-chloroperbenzoic acid, hydrogen per-oxide, peracetic acid, etc., a halogen such as iodine, bromine, etc. or the like in a halogenated hydrocarbon such as dichloromethane, chloroform, etc. -or a polar solvent such as water, acetic acidr methanol, etc. at -20 C to 100 lO C, a compound of the above formula (I) in which R6 or R7 is ~SOmR15 (wherein m represents 1 or 2, and R15 is as defined in the formula (I) ) can be prepared.
Further, for example, by reacting the compound represented 15 by the formula (VI) with a C1-Cs alkyl copper complex prepared from a 0.5 to 5 equivalent amount of c~opper (I) iodide or copper -(I) bromide and a 0.5 to 10 equivalent amount of an organic lithium or oryanic magnesium compound such as C1-Cs alkyl lithium, C1-Cs alkyl magnesium bromide, 20 etc_ in a suitable solvent such as diethyl ether, tetra-hydrofuran, etc. at -lO0 ~ to +100 C for 5 minutes to 24 hours, a co~pound of the formula (I) in which R6 or R7 is represented by a C1-Cs alkyl group can be prepared.
25 Further, for example, by, if necessary, after deprotection, oxidizing the following compound (XII) which can be pre-paréd by reacting the compound (V) or a compound obtained by protecting the hydroxv group of the compound (V) by a suitable protective group, with (X), (XI) or the alkyl 30 copper complex which are the above compounds in a suitable solvent such as water, etbanol, tetrahydrofuran, benzene, dimethylsulfoxide, etc. at -100 C to +200 C for 5 minutes to 48 hours, a compound of the formula (I) in which R6 or R7 is represented by a hydrogen atom can be prepared 35 (Scheme 3).
2~9~
.
7 R I ~R7a ~ C (~?3 )=I~:~.R
ProteCtior of hydro~ group ) or or 10 - Cl-C5 alkyl co~per con~plex 2 R I oR
R ~X=0R~s R~
2 I Rs R~
1 ~ Deprotec_ ) ~- - , r I ) ~) Oxidation (Scheme 3) (wherein Rl, R2, R3, R4, R5 and Ra are as already defined, R28 represents a hydrogen atom, a 1-ethoxyethyl group, a tetrahydropyranyl group, a dimethyl-tert-butylsilyl group, etc , R29 represents SOlR15 (wherein l represents 0 or 2, 25 and Rl5 represents already defined one. ) As the protective group, there may be mentioned a 1-ethoxy-ethyl group, a tetrahydropyranyl group, a dimethyl-tert-butylsilyl group, a benzyl group, etc., and as the oxida-30 tion conditions, the oxidation conditions from the compound(V) to (VI) used in Scheme 1 can be used.
Further, for example, when a compound of the formula (V) in which R8 is represented by ~7~
.
N~?30 ~3 ~ 73 5 [wherein R22 and R23 are as defined in the formula (I), and R30 and R31 each independently represent a hydrogen atom, a C1 to Cs alkyl group which may be substituted by a phenyl group or a Ci to C5 alkylamino group, a phenyl group which may be substituted by a halogen atom or a C1 to Cs alkyl 10 group or a C3 to Cg cycloalkyl group, or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27- (wherein R27 is as defined in the formula (I) ), or a C3-C6 alkylene group which may be substituted by a C1-C5 alkyl group. ] or ~<0~37 (wherein R22 and R23 are as de~ined in the formula (I), and 20 R32 rep~esents a hydrogen atom or a C1-C5 alkyl g~oup which may be substituted by a phenyl group ) is reduced and then o}~idized as shown in the f ollowing Scheme 4, a compound in which R6 = R7 = H among the compounds represented by the above f ormula ( I ) can be prepared .
(Scheme 4) R I OH
(V ) ~ ~\ ( O ) R Rs R~
(wherein Rl, R2, R3, R4, R5 and R8 are as already defined. ) As a reducing agent, there may be mentioned a metal hydride 35 complex compound such as lithium aluminum hydride, etc., 2~7~9~4 and as an oxidizer, there may be mentioned a metal oxidizer such as active manganese dioxide, chromic acid, etc.
2 ) ( Scheme 5 ) Rl 0 R~
R2~,~ T o~\R8 ~ I ) R3 Rs ~Xl I 1) (Xi~') (wherein Rl to R8 are as defined in the formula (I) . ) Further, for example, by condensing the compounds repre-15 sented by the above formulae (XIII) and (XIV) in a suitablesolvent such as ethanol or benzene, etc. in the presence or in the absence of a 0 . 01 equivalent amount to 10 equivalent amount of an acid, a base or a salt as shown in Scheme 5, it can be prepared. As the acid ~:o be used, there may be 20 mentioned a protonic acid such as sulfuric acid, para-toluenesulfonic acid, etc., a ~ewis acid such as boron trifluoride, etc., and the like. As the base and the salt, there may be mentioned ammonia or a salt thereof, an organic base such as piperidine, pyridine, morpholine, 1, 8-25 diazabicyclo-[5,4,0]-undeca-7-ene, etc. or a salt thereof, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc,, a metal amide such as lithium diisopropylamide, etc., a metal alcoholate such as sodium methylate, etc., an alkali metal hydride such as sodium 3 0 hyd~ide, etc ., and the like.
3) Further, for example, a compound in which R6 and R7 are hydrogen atoms or Cl-Cs alkyl groups, and R8 is represented by -COR16 (wherein R16 is as defined in the 35 formula (I) ) particularly among the compounds of the ~} ~q~ ~
.
formula (I) can be prepared according to the following Scheme 4 P~ RG ~ H 2~{R?)~ H R330H ( T ) C~ V~
~? / ( Scheme 4 ) R2~ \~\û /
R L~r7i~; acid (wherein R1, R2, R3, R4, R5, R6, R7, R17 and R18 are as 15 already defined, and R33 represents a Cl-Cs alkyl group which may be substituted by a phenyl group ) For exa~le, by reacting the acetophenone derivative represented by the above formula (XIII) with glyoxylic acid 20 without a solvent or in a suitable solvent including a hydrocarbon type solvent such as benzene, toluene, etc, an ether type solvent such as tetrahydrofuran, dioxane, etc, and the like in the presence of a catalyst including an organic acid (the organic acid can also serve as a solvent) 25 such as acetic acid, propion~c acid, etc, an inorganic acid such as sulfuric acid, phosphoric acid, etc, and the like or without a catalyst at a temperature of -50 ' C to 200 C, preferably 20 C to 150 C for 5 minutes to 48 hours, preferably 30 minutes to 5 hours, the benzoylacrylic 30 acid represented by the formula (XIV) can be prepared Further, the compound (XIV) can be also prepared by, for example, reacting the benzene or benzene derivative represented by the formula (XV) with a maleic acid anhy-dride derivative in the presence of a catalyst such as 35 aIuminum chloride, tin (II) chloride, etc (under condi-tions of the so-called Friedel-Crafts reaction) 2 ~
.
By condensing a compound represented by the f ollowing formula (XV) or (XVI):
R17 Rl 8NH ( XV ) R330H (XVI) (wherein R17 and R18 are as already defined, and R33 repre-sents a C1-Cs alkyl group which may be substituted by a phenyl group. ) 10 to the compound (XIV) in a suitable sDlvent such as tetra-hydrofuran, benzene, dimzthylformamide, etc. or without a solvent in the presence or in the absence of a condensing agent, the compound of the present invention represented by the formula (I) can be prepared. As the cDndensing agent, 15 there may be mentioned the above acids and bases, and also an inorganic ~on~ n~ing agent such as phosphorus oxychlo-ride, thionyl chloride, etc., an organic c~-nfl~n~ing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc., and the like.
Further, for example, after the compound (XIV) is reacted with thionyl chloride, phosphorus pentachloride or the like to be converted into an acid halide, or after ethyl formate, isobutyl formate or the like is made to act on the 25 above compound (XIV) in the presence Df an organic base such as triethylamine, pyridine, etc. to be converted into an active mixed acid anhydride, by reacting said halide or anhydride with the compound (XV) or (XVI) in the presence of an organic base such as triethylamine, pyridine, etc. or 30 an inorganic base such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, etc., the compound represented by the above formula (I~ can be also prepared.
Further, among the compounds represented by the above 35 formula (I), a compound in which the groups represented by R1 to R5 are -OH can be also prepared from the compound (I) in which corresponding R9 is a C1-Cs alkyl group which may be substituted by a halogen atom or a phenyl group, in a ?I~,~ql~
suitable solvent such as methylene chloride, acetonitrile, etc under dealkylation co~ditions that boron trichloride, trimethylsilane iodide, an anhydrous aluminum chloride-pyridine complex or the like is made to act.
Among the compounds represented by the above f ormula ( I ), a compound in which R8 is represented by CN can be also prepared by a dehydration reaction in which a compound in which R8 is represented by -CON~2 is reacted with thionyl 10 chloride, dicyclohexylcarbodiimide, acetic anhydride or the like in a suitable s~lvent such as dimethylformamide, dimethylsulfoxide, etc~ or without a solvent.
~he compound represented by the above ~ormula (I) of the 15 present invention or a salt thereof is useful as a tyrosine kinase inhibitor as described below, and based on its effect, there can be expected uses as a carcinostatic agent, an immunosuppressant, a platelet aggregation inhibiting agent, an arteriosclerosis treating agent, an 2 0 an t i -; n f 1 A ImnA t ory agen t, e t c .
As a preparation of the tyrosine kinase inhibitor or the carcinostatic agent according to the present invention, any preparation by oral, enteral or parenteral administration 25 can be selected. As a specific preparation, there may be mentioned a tablet, a capsule, a fine granule, a syrup, a suppository, an ointment, an injection, etc.
As a carrier o~-the tyrosine kinase inhibitor or the 30 carcinostatic agent according to the present invention, there may be used an organic or inorganic,- solid or liquid and generally inactive pharmaceutical carrier material which is suitable for oral, enteral and other parenteral administrations Specifically, there are, for example, 35 crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fat and oil, gum and 2 ~ 7 ~
.
polyalkylene glycol. The ratio of the tyrosine kinase inhibitor or the carclnostatic agenf: of the present inven-tion to the carrier in the preparation can be changed at a ratio of 0 2 % to 100 96.
Further, the tyrosine kinase inhibitor or the carcinostatic agent according to the prese~t invention may contain a tyrosine kinase inhibitor or a carcinostatic agent which is different therefrom, and other medicines. In this case, 10 the tyrosine kinase inhibitor or the carcinostatic agent according to the present invention may not be a main ingre-dient in the preparation.
The tyrosine kinase inhibitor or the carcinostatic agent 15 according to the present invention is administered generally in a dose by which a desired effect can be achieved without side effect. A specific value thereof should be r~et~rm;n~l by judgment of a doctor, but it is generally 10 mg to 10 g, preferably 20 mg to 5 g per day in 20 the case of an adult. The compound of the present inven-tion may be administered in a dose of 1 mg to 5 g, more preferably 3 mg to 1 g per day in the case of an adult as an active ingredient.
25 Best mode for practicing the invention In the following, the present inven'.ion is described in detail by referring to Examples and ~est example, but the present invention is not limited by the following examples 30 unless it exceeds its scope.
Example 1 O O
~CH3 --i 'COOH
2 ~
.
a,7 Under nitrogen atmosphere, a solution of 3, 4-dimethoxy-acetophenone (10.00 g, 56 mmol) and glyoxylic acid mono-hydrate (5.11 g, 56 mmol) dissolved in 11 ml of acetic acid was refluxed unaer heating for 20 hours. The reaction 5 mixture was cooled, and the precipitated solid was collected by filtration, washed with acetic acid and then dried by heating to give 7.75 g (yield: 59 %) of the above carboxylic acid.
m.p. 175 to 177 C
1H NMR (DMSO, 250 MHz) ~ ppm: 3.86 (s, 3H), 3.89 (s, 3H), 6.68 (d, lH, J=15 4Hz), 7.11 (d, lH, J=8.5Hz), 7.51 (d, lH), 7.77 (dd, lH, J1=2.0Hz, J2=7.8Hz), 7.94 (d, lH, .J=15 . 5Hz ) .
Example 2 O O
L~ DX~ 0 HA
I,I~O~o To a suspension of the above carboxylic acid (1.5 g, 6.36 mmol) obtained in Example 1 in 10 ml of carbon disul Eide was added phosphorus pentachloride ( 1. 6 g, 7 . 63 mmol ), and 30 the mixture was refluxed under heating for 15 minutes. A
solution of the residue obtained by cooling and then concentrating the reaction mixture, dissolved in 5 ml of dichlorom~thi~n~ Mas added to 5 ml of concentrated aqueous ammonia under ice cooling. The precipitated solid was 35 collected by filtration, washed with 1 N NaOH and water in ~ ~J7i~9~4 this order and then dried to give 900 mg (yield: 60 %) of an a~[ide compound.
m.p. 188 to 190 C
lH NMR (250 ~XZ, D~SO) ~ ppm: 3.85 (s, 3H), 3.88 (s, 3H), 6.95 (d, lH, .J=15.3HZ), 7.12 (d, lH, J=9.3Xz), 7.51 (s, 1~l), 7.54 (s, lH), 7.76 (d, lH, J=8.7Hz), 7.82 (d, lH, J=15.5Hz), 7.85 (s, lH):
10 A dimethylformamide solution (5 ml) of the amide compound (500 mg, 2.13 mmol) was stirred on an ice bath, and thionyl chloride (0.31 ml, 4.2 m.~ol) was added thereto. After the mixture was stirred at room temperature for 20 minutes, water was added to the reaction mixture, and the product 15 was extracted with ethyl acetate The resi~ue obtained by washing the extract with brine was dried (anhydrous magne-sium sulfate), conce~trated and recrystallized ~rom hexane-ethyl acetate to give a desired nitrile compound (220 mg, 47 %).
m.p. 132 to 135 'C, pale orange- crystal H NMR (250 ~![Hz, CDC13) ~ ppm: 3.96 and 3.99 (2s, 6H), 6.57 (d, J=16.0HZ, lH), 6.95 (d, 3=8.3HZ, lH), 7.50 to 7.70 (m, 2H), 7.84 (d, J=16.0Hz, lH) .
25 IR (1~}3r) cm~l: 3000, 3036, 2222, 1664, 1609, 1582, 1520, 1354, 1277, 1128, 772.
Exampl e 3 ~leO C~)7~ 71~e To a dichloroethane solution ( 6 ml ) of the carboxylic acid (1.00 g, 4.24 mmol) obtained in Example 1 were added methanol (0.52 ml, 12.72 mmol) and concentrated sul:Euric ~ 9 1 ~
acid (0.014 ml), and the mixture was refluxed under h-eating ~or 2 hours. Water was added to the reaction mixture, the product was extracted with ethyl acetate, and the extract was washed with a saturated jodium hydroyen carbonate 5 a~aueous solution and then dried (anhydrous magnesium sulfate) ~rnder reduced pressure, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (developing solution: n-hexane/ethyl acetate = 5~1) to give a desired methyl ester compound (610 mg, 57 9~
m.p. 90 to 93 C, pale yellow crystal H N~qR ~250 MHz, CDCl3) ~ ppm: 3.85, 3.96 and 3 98 (3s, 9H), 6.89 (d, J=15.5Hz, lH), 6.93 (d, J=8.4Hz, lH), 7.58 (d, J=2.0Hz, lH), 7 66 (dd, J=2.0, 8.4H2, lH), 7.95 (d, J=15 5H2, lH) .
IR (~Br~ cm~l: 2944, 2851, 1721, 1665, 1622, 1580, 1449, 1420, 1306, 11S5, 1019, 766.
20 Example 4 D D
) 0~ O~h' ~20 1~20 By using 4-methoxyacet-)rh~none as a starting substance, the above methyl 2-(4-methoxybenzoyl)acrylate was obtained by the same method as in Example 1 and Example 3 (overall yield: 20 9~;).
m.p 75 to 76 C, pale yellow crystal IR (KBr) cm~l: 2948, 2847, 1717, 1669, 1626, 1595, 1512, 1447, 1339, 1308, 1263, 117I, 986, 837, 768, 596.
35 Example 5 ~ ~7~8~4 O O
OHC-C02H ~--CD2M -- *
o ~CO~lHPh 10 By using propiophenone as a starting substance, a reaction was carrled out by the same method as in Example 1 to obtain a corresponding carboxylic acid (yield: 29 ~6). A
tetrahydrofuran solution (20 ml) of this carboxylic acid (1.04 g, 5.54 mmol) was stirred under nitrogen atmosphere, and triethylamine (0.97 ml, 7.0 mmol) and aniline (0.64 ml, 7 . 0 mmol) were added thereto. The reaction mixture was cooled on an ice bath, phosphorus oxychloride (0.78 ml, 8.4 mmol) was added thereto, and the mi2~ture was stirred at room temperature overnight. Water was slowly added to the 20 reaction mixture, the mixture was concentrated under reduced pressure, -water was further added to the concen-trate, and the product was extracted with ethyl acetate (70 ml). The extract was washed success~vely with a saturated sodium hydrogen carbonate aqueous solution, ~[iluted hydro-25 chloric acid and water and dried over anhydrous sodiumsulfate. Under reduced pressure, the solvent was removed by evaporation, and the obtained solid was recrystallized from ethanol-water to give the desired above-mentioned amide compound (170 mg, 11 %).
H N~ (250 MHz, CDCl3) ~ ppm: 2.45 (d, J=1.3Hz, 3H), 6.26 (q, J=1.3Hz, lH), 7.13 (t, J=7.4Hz, lH), 7.33 (t, J=7.4Hz, 2H), 7.40 to 7.65 (m, 6H), 7.75 to 7.85 (m, 2H).
m.p. 128 to 129 C, colorless needle crystal Example 6 2~8~
O O
[~~1~ ~) E~3N ~
Under nitrQgen atmosphere, methanol (6 ml) was cooled to -20 'C, and 0.34 ml (4.7 mmol) of thionyl chloride was added thereto. Aiter the temperature o~ the solution was raised to -lO Cr the above carboxylic acid (560 mg, 3.14 10 mmol) synthesized by the method o~ R E Lutz et al. [J. Am.
Chem. Soc., 75, 5039 (1953) ] was added thereto. The mixture was stirred at room temperature lor 3 days and then concentrated under reduced pressure to give an exo-methyl-ene methyl ester compound (450 mg, 70 %) . To an ether 15 solution (6 ml) of this exo-methylene=methyl ester compound (360 mg, 1.76 mmol) was added triethylamine (2 ml), and the mixture was stirred at room temperature ~or 5 days. After the mi~ture was con~-Pn~r~t~d under reduced pressure, the residue was puri~ied by applying it to silica gel column 20 chromatography (developing solution: n-hexane/ethyl acetate = 10/1) to give the desired above methyl ester compound (260 mg, 72 %) as an oily substance.
lH NMR (250 MHz, CDCl3) ~ ppm: 2.20 (d, J=1 3Hz, 3H), 3 86 25 (s, 3H), 7.'L5 to 7.65 (m, 3H), 7.73 (q, J=1.3Hz, lH), 7 95 to 8 . 02 (m, 2H) .
Example 7 Z~ ONHPn By using ~he above carboxylic acid synthesized by the 35 method o~ R.E Lutz et al [J Am Chem Soc, 75, 5039 (1953) ~, amidation was carried out by the same method as in Example 5 to give a desired anilide compound (yield: 58 %).
IH NMR (250 MHz, CDCl3) ~ ppm: 2 34 (d, J=1 4Hz, 3H), 7.17 (t, J=7.4Hz, lH), 7 31 to 7 42 (m, 2H), 7.43 to 7.65 (m, 6H), 7.74 (brs, lH), 7 95 to 8.03 (m, 2H) .
m.p 127 to 128 C, pale yellow columnar crystal Example 8 D
i * ~ [~(CH3~=c(cH~)G~N3~h 20 By using the abo~re lactone compound synthesized according to the method of R.E. Lutz et al. [J. Am. Chem. Soc., ~, 5039 (1953) ], amidation was carrled out by the same method as in Example 5 to give a desired a~ilide compound (yield:
73 %)-H NMR (250 MHz, CDCl3) ~ ppm: 1 85 and 1.89 (2d, J=0 8Hz, 6H), 6 . 73 (m, 2H), 6 . 85 ( t , J=7 . 4Hz , 1H), 7 . 11 ( t , J=7 . 9Hz , 2H), 7 . 37 (m, 3H), 7 . 52 (m, 2H) .
m.p. 218 to 221 C, white crystal Example 9 H
B r ` ~ J~
NH . -- - ~ ~N
\1/ \1/
2 1 ~ ,g~
Under nitrogen atmosphere, an acetone suspension (15 ml) oE
diisopropylamine (4.05 g, 40.0 mmol) and potassium carbonate (6.91 g, 50.0 mmol) was cooled to 5 'C, and while stirring the suspension, propargyl bromide (3.01 ml, 40.0 5 mmol) was added thereto. After the temperature of the reaction mixture was raised to room temperature over 2 hours, the mixture was further stirred at room temperature for 3 honrs. To the residue obtained by removing precipi-tates by filtration and concentrating the filtrate was 10 added water, and the product was extracted with dichloro-methane (50 ml). After the extract was dried over sodium sulfate, the solvent was removed by evaporation under reduced pressure to give oily propargylamine (2.78 g, yield: 50 %).
H NMR (250 MHZ, CDCl3) ~ ppm: 1.10 (d, J=6.5HZ, ~2H), 2,13 (t, J=2.5HZ, lH), 3.20 (hep, J=6.5HZ, 2H), 3.42 (d, ~=2 . 5HZ, 2H) .
Example 10 H ~ 0 \1/ ~eO~
~
Under nitrogen atmosphere, a tetrahydrofuran solution (40 ml) of the propargylamine (1.39 g, 10.0 mmol) obtained in Example 1 was cooled to -70 C, and while stirring the solution, a 1. 56 M n-butyl lithium solution was added 30 dropwise thereto. After the temperature of the reaction solution was slowly raised to O C, the solution was cooled to -70 C/ and a tetrahydrofuran solution (10 ml) of 3,4-dimethoxybenzaldehyde (1.66 g, 10.0 mmol) was added drop-wise thereto. After the temperature of the reaction 35 mi2~ture was raised to O C over 2 hours, water was added thereto to terminate the reaction. Unaer reduced pressure, 2 ~ 4 .
the solvent was removed by evaporation, and then the product was OEtracted with dichloromethane ~40 ml x 2).
After the extract was dried over: anhydrous sodium sulfate, the solvent was removed by evaporation under reduced 5 ~)L~ U.C'c:. The residue was purified by silica gel column chromatogre~phy (CHCl3: MeOH = 20: 1) to give the above-mentioned amino-alcohol (3.00 g, yield: 98 ~6) as an oily subs tance .
10 lH ~R (250 3~Hz, CDC13) ~ ppm: 1.10 (d, J=6.5Hz, 12H), 2.40 (brs, lH), 3.20 (hep, J=6.5Hz, 2H), 3.51 (d, J=1.7Hz, 2H), 3.89 and 3.90 (2s, 6H), 5.42 (brs, 1~), 6.85 (d, J=8.1Hz, lH), 7 . 07 (m, 2H) .
15 Example 11 Dll D~l A tetrahydrofuran solution (10 ml) of the propargyl alcohol (1.02 g, 3.10 mmol) obtained in Example 10 was added drop-wise to an ether solution (30 ml) of 330 mg (8.7 mmol) of lithium aluminum hydride cooled to -30 C. After the 25 mixture was stirred at room temperature for 2 days, water (1 ml) was slowly added to the react-on mi~ture while ice cooling . Af ter the mixed solution was stirred at room temperature for a while, insolubles was filtered with celite, and the filtrate was concentrated. The residue was 30 purified by silica gel column chromatography (developing solution: chloroform/methanol = 30/1 to 5/1) to give an allyl alcohol compound (719 mg, 76 %).
lH NMR (250 lMHZ, CDC13) i~ ppm: 1.05 (d, J-6.6Hz, 12H), 2.10 35 (brs, lH), 3 11 (hep, ~=6.6Hz, 2H), 3.13 (d, J=3 8Hz, 2H), 2 ~
.
3 87 and 3 38 (2s, 6X), 5 .17 (m, lH), 5 83 (m, lH), 6 . 80 to 6 . 95 (m, 3H) .
Example 12 OH
MeO ~ ~ ) MnO
A'eOf~J ~~ ~) HO
/~
~eO~O
MeO
15 A dichloromethane solution (50 ml) of the allyl alcohol compound (710 mg, 2 . 32 mmol) synthesized in Example 11 was vigorously stirred at room temperature, and active man-ganese dioxide (7.1 ~) was gradually added thereto. After stirring was continued for 1.5 hours, the reaction mixture 20 was filtered with celite, and the filtrate was concentrated to give a ketone compound ( 45 0 mg, 64 % ) .
H NMR (250 MXz, CDCL3) ~ ppm: 1 03 (d, J=6.5Hz, 12H), 3.06 (hep, ,J=6 5Hz, ~H), 3.34 (d, ,J=4 4Xz, 2H), 3.95 (s, 6H), 6.91 (d, J=8.2Hz, lH), 7.06 (dt, J=15.1, 4 4Xz, lH), 7 19 (d, J=15.1Hz, lH), 7.55 to 7.65 (m, 2H) .
An ether solution ( 8 ml ) of the obtained ketone compound (116 mg, 0 38 mmol) was cooled with ice, a 7 % by weight of 30 hydrogen chloride acetic acid solution (0.7 ml) was added thereto, and the mixture was stirred at the same tempera-ture for 15 minutes Precipitated amine hydrochloride (109 mg, 84 96) was isolated by filtration.
lH MMR (250 MHz, D~So-d~ ~ ppm: 1 33 and 1.36 (2d, J=ll OHz, 12H), 3 69 (m, 2H), 3 85 and 3 87 (2s, 6H), 4.10 217~
(m, 2H), 7.05 (dd, J=6.8, 15.1xz, lH), 7.13 (d, J=8 5Hz, lH), 7.53 (d, J=1.7Hz, lH), 7.65 to 7.80 (m, 2H) .
Example 13 H - - ~) MeO ~ " N~
10 By using 3-piperidinepropyne (Japanese Provisional Patent PublicatiDn Mo. 9~755/1979) as a starting substance, the a'Dove amine compound was obtained by the same method as in Examples 10 to 12 (overall yield: 20 %).
lH MMR (250 MHz, CDCl3) ~ ppm: 1.40 to 1.55 ~m, 2X), 1.62 (m, 4H), 2.45 (m~ 4H), 3.22 (m, 2H), 3.95 and 3.96 (2s, 6H), 6.90 (d, ~=8.3Hz, lH), 7.00 to 7.10 (m, 2H), 7.50 to 7.70 (m, 2H) .
20 To an acetone solution (5 ml) of the obtained amine com-pound (360 mg, 1.30 mmol) was added an acetone solution (10 ml) of fumaric acid (75 mg, 0 . 65 mmol), and the mixture was stirred at room temperature for 30 minutes. The precipi-tated crystal was collected by filtration and washed with 25 acetone :t-o give fumarate of the above amine compound (180 mg, 35 %)-H MMR (250 MHz, DMSO-d) ~ ppm: 1.35 to 1.50 (m, 2H), 1.50 to 1.63 (m, 4H), 2.45 to 2.65 (m, 4H), 3.34 (d, J=6.3Hz, 2x), 3.81 and 3.84 (2s, 6H), 6.57 (s, 2H), 6.83 (dt, J=15 3, 6.3Hz, lH), 7.07 (d, J=~.5xz, lH), 7.30 (d, J=15.3Hz, lH), 7.47 (d, J=1.8Hz, lH), 7.67 (dd, J=1.8, 8 . 5E~z, lH ) .
m.p. 143 to 144 ~C~ colorless powder crystal 21~9~4 IR (Ksr) cm~1: 3449, 2946, 2773, 2596, 1671, 1626, 1581, 1518, 1424, 1393, 1354, 1277, 1242, 1204, 1157, 1022, 766, 632 _ 5 E~ample 14 OH O
~ NeOX~ --N --O SPh lleO~ ~ N
I(eO
A dichloromethane solution (50 ml) of the amino-alcohol (1,20 g, 3.93 mmol) obtained in Example 10 was vigorously stirred at room temperature, and active manganese dioxide (12.0 g) was added to this solution. After 1 hour, 20 insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to give the above ynone compound (715 mg, yield: 60 %) which was a desired com-pound, as a brown oily substance.
o S ~eO~
~(eO ~
lH NM~ (250 MHz, CDCl3) ~ ppm: 1.16 (d, J=6.5Hz, 6H), 3.27 (sep, J=6.5Hz, lH), 3.73 (s, 2H), 3.94 and 3.97 (2s, 6H), 6.94 (d, J=8.5, lH), 7.62 (d, J=1.8Hz, lH), 7.84 (dd, J=1. 8, 8 . 5Hz, lH) .
To an ether solution (5 ml) of the obtained ynone compound (320 mg, 1.05 mmol) were added thiophenol (110 111, 1.07 mmol) and a trace amount of piperidine, and the mixture was ' 58 stirred at room temperature for 4 hours. Under reduced pressure, the mixture was concentrated, and the residue was purified by silica gel column chromatography (developing solution: n-hexane/ethyl acetate = 2/1) to give a thio-5 phenol adduct (219 mg, 50 %) which was a desired substance.
O SPh J~l~eO~ ~ N
~leO
H NMR (250 MHz, CDCl3) ~i ppm: 0.91 (d, J=6.6Hz, 12H), 2.97 (hep, J=6.6Hz, 2H), 3.02 (d, J=1.4Hz, 2H), 3.96 (s, 6H), 6.93 (d, J=3.3Hz, lH), 7.35 to 7.g5 (m, 3H), 7.55 to 7.70 (m, 4H), 7.81 (t, J=1.4Hz, lH) .
m.p. 120 to 122 C, pale yellow crystal Example 15 ~eO~ N
~(eO `f l~eO~CH=C(~iO2Ph)CH~Y
To an ethanol solution (4 ml) of the ynone compound (120 mg, 0.38 mmol) obtained in Example 14 and sodium benzene-sulfinate (76 mg, 0.38 mmol) was added acetic acid (25 ~
0.42 mmol) at room temperature, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added water (10 ml) and saturated sodium hydrogen carbonate (10 ml), and the product was extracted with chloroform (20 ml). The extract was dried (anhydrous 2~ 789~
~9 (anhydrous sodium sulfate) and concentrated, and the residue was purified by silica gel chromatography to give the desired above-m~n~;on~1 vinyl sulfone compound (93 mg, 55 96).
50 ~0 ~h J`
~0 10lH NMR (250 MHz, Cr)Cl3) ~ ppm: 0.90 (d, J=6 5Hz, 12H), 2.95 (hep, J=6.5H7, 2x), 3.32 (s, 2H), 3.95 and 3.97 (2s, 6H), 6.94 (d, J=8.4Hz, lH), 7.42 (brs, lH), 7.45 to 7.70 (m, 5H~, 7 . 96 to 8 . 05 (m, 2H) .
m.p. 167 to 169 ~, orange powder crystal IR (K33r) cm~l: 2972, 1651, 1586, 1514, 1466, 1421, 1318, 1271, 1213, 1173, 1146, 1088, 1017, 762, 729, 615, 602, 557 .
Example 1 6 O O
~1~0~ \~ o~N
~r~der nitrogen atmosphere, to a tetrahydrofuran solution (15 ml) of cuprous cyanide (179 mg, 2 . 0 mmol) was added dropwise a 1.5 M methyl lithium ether solution (2 7 ml, 4.0 mmol) at -50 C, and the mixture was stirred for 2 minutes.
The solution was cooled to -70 C, and a tetrakydrofuran solution (6 ml) of the ynone compound (289 mg, O.9S mmol) obtained in Example 14 was added dropwise thereto . Af ter tke temperature of the reaction mixture was slowly raised to roolll temperat~ure, the mixture was cooled to 0 ' C, and a saturated ammonium chloride aqueous solution and aqueous ammonia were added thereto. After the product was extracted with ether (20 ml x 2) and dried (anhydrous ~ ~ 7~
sodium sulfate), the solvent was removed by evaporation ul~der reduced pressure. ~he residue was purified by silica gel column chromatography (developing solution: n-hexane/
echyl acetate = 2/1) t~ give the above-mentioned desired 5 compound (160 mg, 53 %) as an oily substance.
O .~.c ~I ~ D ,~
11~0/~ --1' H NMR (250 MXz, CDCl3) ,S ppm: 1.03 (d, J=6.6Hz, 12H), 2.11 (s, 3H), 3.0~ (hep, J=6.6Xz, 2X), 3.15 (s, 2H), 3.95 (s, 6H), 6.91 (d, ~=8.1Hz, lH), 7.23 (m, lH), 7.57 (s, lH), 7.59 (dd, J=1.9, 8.1Hz, lH) ~xample 17 - -o ~ X~Et ~ ~[eO < ~IEt ~
By using the above-m.onti r. nr~rl 3- (diethylamino) -3-methyl-butyne prepared according to the method of A. P . Poisselle et al. [J. Org Chem., 26, 725 (1961) ~ and the method of R.S Xznze1 et al. [J Am Chem. Soc., 82, 4908 (1960) ] as a starting substance, the above-mentioned amine compound was obtained by the same me~hod as in Examples 10 to 12 (overall yield: 59 96) .
a U~O~>< NE~7 Inr~O
lH NMR (250 MXz, CDCl3) ,S ppm: 1 06 (t, J=7.1Hz, 6H), 1 28 35 (s, 6H), 2.58 (q, J=7.1Hz, 4H), 3.95 and 3.96 (2s, 6H), 21~8914 .
6.87 (d, J=15.7Hz, lH), 6.91 (d, J=8.0Hz, lH), 7.09 (d, J=15.7Hz, lH), 7.55 to 7.62 (m, 2H) P~n ether solution of the above-mentioned amine compound obtained (100 mg, 0 33 mmol) was cool~d with ice, a 7 96 hydrochloric acid ethyl acetate solution (2 ml) was added thereto, and the mixture was stirred at the same tempera-ture for 15 Tninutes The precipitated solid was collected by filtration and dried to give hydrochloride of the above-mentioned amine compound (75 mg, 67 %) .
o ~~X N~t~
1~0 ~{C
H MMR (2~0 r~Hz, CDCl3) ~ ppm: 1.57 (t, J=7.4Hz, 6H), 1.83 (s, 6H), 3.05 and 3.46 (2m, 4H), 3.97 and 3.99 (25, 6H), 6.96 ~d, J=8 5Hz, lH), 7.11 (d, J=15.7Hz, lH), 7.63 (d, J=15.7Hz, lX), 7,63 (d, J=1 9Hz, lH), 7.77 ~dd, J=l.9, 20 8.5Hz, lH), 11 82 (brs, lH) .
m.p. 214 to 215 '~, white powder crystal Example 18 x~ D <~
By using 3-piperidine-3-methyl-butyne as a starting 30 substance, the above-mentioned amine compound (overall yield: 24. %) and hydrochloride (yield: 73 %) were obtained by the same method as in Example 17 The respective da~a are shown belo~.
.
~leO I ~, / ~, ~3 ~eO
H NMR (250 MHz, CDCl3) ~ ppm: 1.25 (s, 6H), 1.40 to 1.50 (rn, 2H), 1.50 to 1 65 (m, 4E~), 2.53 (m, 4H), 3.95 and 3.96 (2s, 6H), 6.88 ~d, J--15.4Hz, lH), 6.91 (d, 3=8.0Hz, lH), 7.C7 (d, J=15.7Hz, lH), 7.50 to 7.62 (m, 2H) .
10 Pale yellow oily substance ~leO~
~eO
~ C s~
H MM~ (250 MHz, CDCl3) ~ ppm: 1.79 (s, 6H), 1.80 to 2.00 (m, 4H), 2.45 to 2.80 (m, 4H), 3.60 to 3 75 (m, 2H), 3.97 a~d 3.99 (2s, 6~), 6.96 (d, J=8 4Hz, lH), 7.07 (d, J=15.7Hz, lH), 7.54 (d, J=15.7Hz, lH), 7.62 (d, J=1.9Hz, lH), 7.75 (dd, J=l.9, 8 4Hz, lH), 12.10 (brs, lH) .
m.p. 255 'C (dec~, colorless powder crystal E}~ample 1 9 ~ X~IE L 2 ~ U ~O~ E ~, 3 0 ~I~D~J~C~=C (S02 ~h) l~e 0 7\~E t 2 By using 3-dimethylamino-3-methylblltyne as a starting 35 substance, the above-mentioned ynone compound was synthesized (see E2~ample 10 and Example 14, overall yield:
2 ~ ~89 ~ ~
64 ~), and further a vinyl sulfone compound (yield: 46 %) was obtained by the same method as in Example 15.
O
ILoO~
l~J ~ NEt l~I ~R (250 MHz, CDCl3) ~ ppm: 1.13 ~t, J=7.1Hz, 6H), 1.54 (s, 6H), 2.78 (q, J=7.1Hz, 4H), 3.95 and 3.97 (2s, 6H), 6.94 (d, J=8.gHz, lH), 7.63 (d, J=1.9Hz, lH), 7.84 (dd, J=1 9, 8 . 4Hz, lH) .
~ ~(e~ ~S0 Pn lH NMR (250 MHz, CDCl3) ~ ppm: 0.96 (t, ~J=7.1Hz, 6H), 1.35 (s, 6H), 2.91 (q, J=7.1Hz, gH), 3.96 ~s, 6H), 6.96 (d, ~=8.2Hz, lH), 7.45 to 7.70 (m, 5H), 7 84 (s, lH), 8.05 to 8 . 10 (m, 2H) .
m.p. 133 to l3a C, pale yellow powder crystal IR ~K}3r) cm~l: 2975, 2938, 1655, 1597, 1586, 1512, 1449, 1418, 1306, 1269, 1209~ 1169, llg6, 1086, 1020, 756, 741, 69g, 6g2, 561.
Reference example 1 ~_5Q C ~ ~ ~SC~ila 20 ml of an aqueous solu~ion of sodium sulfite (5.0 g, 39.9 mmol) and sodium hydrogen carbonate (3 . 5 ~, 42 . 0 mmol~ was 35 heated to 80 C by an oil bath, p-toluenesulfonyl chloride (4 0 g, 21. 0 mmol) was added thereto, and the mixture was 7~7~9~
heated at 80 C ~or 4 hours. After cooling, crystal was collected by filtration and dried under reduced pressure.
~he crystal was used for the next reaction without carrying out further purilication. (yielded amount: 2,7 g, yield:
5 7~ ~) ~ SO 2Na 10 lH NMR (250 MHz, DMSO-d6) ~ ppm: 2.29 (s, 3H), 7.12 (d, J=7.9Hz, 2H), 7.38 (d, J=7.9Hz, 2H) .
Colorless powder In the same manner as in Reference ex~nple 1, the co~pounds 15 of Reference e2~Lples 2 to 4 were prepared by usin~ commer-cially available sulfonic acid chlorides. In the follow-ing, the structures of the used acid chlorides and the desired compounds and the physical properties and yields of the desired compounds are shown.
Refer- Sulfonic Sodium 1H-NMR (250 Yield e~nple acid sulfinate MHz, DMSO-d6) 7 . 71 (d, J=
~2~S02CI N02~so2N~ 8 12 (d, J- 69 8.6Hz, 2H) - 6.92 to 6.97 3 ~1 ~1 (m, 2H), 7 40 75 ~S/~SO2Cl ~S~SO2Na (d, J=4 5Hz, 4 MeS02Cl MeS02Na 1.95 (s, 3H) 20 Example 20 ~o ,11~
~leOX~ ~NE~ 2 o .I~IeO~J!~cH-c(so2c6H4-p~e)c~e2NE~2 lleO
Acetic acid (75 ml, 1.32 mmol) was added to an ethanol solution (10 ml) of the ynone compoun~ (400 mg, 1.32 mmol) obtained in Example 19 and sodium p-toluenesulfinate (350 mg, 1.98 mmol) obtained in Reference example 1 at room lQ temperature, and the mixture was stirred at room tempera-ture for 24 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, then 20 ml of water was addea to the concentrate, and the mixture was extracted twice with each 20 ml of chloroform. The organic 15 layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated saline solution, dried over anhydrous sodium sulfate and then filtered. The residue obtained after concentration under reduced pressure was applied to silica gel column chromatography (n-hexane-20 ethyl acetate = 3: 1) to give a vinyl sulfone compound(280 mg, 46 %) from a desired fraction.
o lleoX~CH=C(S02C6H4-P~le)CYe2~et2 NMR (250 MHz, CDC13) ~ ppm: 0.98 (t, J=7.1Hz, 6H), 1.34 (s, 6H), 2.42 (f, J=7.0Hz, 4H), 2.43 (s, 3H), 3.96 (s, 6H), 6.95 (d, J=8.3Hz, lH), 7.33 (d, J=8.1Hz, 2H), 7.50 (dd, J=8.3, l.9Hz, lH), 7.58 (d, J=1.8Hz, lH), 7.82 (s, lH), 7.94 (d, J=8.3Hz, 2H) .
m.p. 75 to 77 C, colorless powder IR (Ksr) cm~1: 2971, 1659, 1595, 1514, 1464, 1418, 1306, 1269, 1144, 1024, 818, 758, 723.
21~14 By using the sodium sulfinates prepared in Reference exam-ples 2 to 4 and the ynone compound obtained in Example 19, the compounds of Examples 21 to 23 were prepared in the same manner as ~n the ~Lethod of Example 20. In the follow-5 ing, the structures of the sodium sulfinates used and thedesired compounds and the physical properties and yields of the desired compounds are shown.
2 ~ 7~9 ~ ~
~ . . .~
~ `-- _ . .
æ ~ ~Uq~ 0~ g _. . . _ ~ -- i -- ~. ,n _ _ --. 2 = ~ _ 2 ~
2 q ~ ~ 0 ~ = ~ = ~ = ~ ~ ~ ~ 2 cn . _ ~ O~ ~ O = G = = o d ,~, _ -o~ r~ !
r - ~ z ~ w '~ r~
c) o o ro~J o o ~ o q 1 4 - , .
D ~ , -- ~ t-`'~
t~ ~ ~ ~ ~ C
C ~
_ _ _ ~ t~ ~
oJ
CO~
L
E ~ .:
o ~ ~
~ ~ZO
2~ 7~91~
By using amino-alcohols prepared from the respective aldehydes and propargylamines in the same manner as in the method of Example 10, ynone compounds were prepared in the same manner as in E7cample la.. By using the o~tained ynone 5 compounds and using sodium benzenesulfinate, the compounds of E~camples 2~ to 28 were prepared in the same manner as in the method of Example 15 In the follo~ing, the structures of the used ynone compounds and the desired compounds and the physical properties and yields of the desired compounds 10 are shown.
2 1 789 l ~
. =, ~ ~ ~r ~ L
S cr: ~ ~ _ ~- ~
~ _ _ _ _ . _ ~ _ _ ~ æ ~ 0 ~ =~ O ~ S--Q
Q
~<
(~ O ~
pUrlOL~IO~I auor;~; puno~ o::~ pallsaa ~ ~ o C~
--q l ~
.
~ , . ~ . ~ i , ,~
o O ~V _ _ _ _ Lr~
cr , q , O c ~ ,_ ~ ~ O O ; ,_ -- r ~l Cq Cq . -- ~ r~ ~ Cq ~ Lq r ~ :~
_ C~ ~ ~ ~ O ~ rr' _~ ~ ~ ~ =
rrr q O = _ .5 _ _ 3 `_ q ~q $
r~ --~ =, ~ ~ ~ . Cq = =-5r rr~ 5 _ 3 ~ -"
_~, æ ~ q ,~
c~ - ~3 q ~r ~r r q ' q ,-- O
' 'q r-- t~
r,~ ~ ~ . W
Q
L Q
"~ o~
o~
o~
~, , . . . .
punoduloa auou~ p-.modlllo~ pallsaa , .
~ 72 .-- . . . ;
a) ~ ~
~ . , . . -~
o ~ ~
33 ~ ~ e U L'~ ~ ~ U ~~) 8C~ q ;~ cL~ ~ 0 ~ G
~ _ C~ N
C ~
~ _ ~ ~ , _ _ _ C~~ O ' ' ~ = ~ =
^ -- -- C 1~
__ _ _ ~ C`~ _ ~ O~ _ -- ~ ~: O 1:-- ~ ~ ~ L" C~ O
Q
..
,~ .
o ~/ ~r \~
o o punodllo~ auor~T,C punodu}oa p~31L5 o -2178~14 o o ~ ~ -- ~ q ~ ~ ~ o o C~ ~ ~ ; O ~ ~ ~ ~ q ~
q q C~ _ ~'~ ~ ~ ~q ~
~ C~
-- o _ o _ C'~ o ~ q c~ C~
C~ ~ C~ O ~ = ~ --~ ' D O - - ' cq -- ~ ~ ~ ~q c--~ -qq o ~
~ ~ ~ $
_ _ t~: r~ -~D C~:-- O ~ 2~i 1 3 _ _ Q
Q
V
,~ o , o~ .
o~
o~
p~oaulo~ ~uou~ puno~o~ p~lS~a ~' ~Z
, . ~ =
3 ", ~ ;~ o Il. O ~ P.~ O
~~_ O ~
- ~ - ~ ~ ~ ~ ~ - ~ o 3 ~ 1-- 0 ~ ~ ~
Q
Q
X G
punoduloa ~3uou~ punoduloa pal~s~3~
o ~
D~ Z =, . , I
2 ~ 7~9 ~ 4 .
Example 2 9 OH
H ~(~o ~
S ~ NfI ~ ,~ XN~
~O ,L~
~0~ X
Molecular sieve 4A (10 g) was added to a tetrahydrofuran solution (50 ml) of 3-amino-3-methyl-1-outyne (S O g, go %
in H20, 54 mmol), and the mixture was stirred under nitro-gen atmosphere for 30 minutes. Under nitrogen atmosphere, the molecular sieve was removed by filtration, and the filtrate was cooled by a dry ice-ethanol bath. To this filtrate was added dropwise a 1.63 M n-butyl lithium hexane solution (33.0 ml, 54.0 mmol) over 2 hours. After the temperature of the reaction mixture was slowly raised to O
C, the mixture was cooled again by a dry ice-ethanol bath, and veratraldehyde (8.97 g, 54 0 mmol) was added thereto.
Af ter the temperature of the reaction mixture was raised to room temperature, the mi~ture was cooled to O C, and water was added thereto to terminate the reaction Af ter the solvent was removed by evaporation under reduced pressure, water was added to the residue, and the product was extracted with dichloromethane (70 ml x 2) . The extract was dried (anhydrous sodium sulfate) and concentrated, and the obtained oily substance was purified by silica gel column chromatography (developing solution: chloroform/
methanol = 50/3) to give amino-alcohol (7 65 g, 57 %) which was an adduct.
3s Amino-~l cohcl coTnnol~ntl 2~78914 lH NMR (CDCl3, 2~0 MHz) ~ ppm: 1.44 (s, 6H, 1.98 (brs, 3H), 3.89 and 3.90 (2s, 6H), 5.41 (s, lH), 6.86 (d, J=8.7Hz, lH), 7 . 03 to 7 .10 (m, 2H) .
m.p. 85 to 87 C, pale yellow crystal At room temperature, to a dichloromethane solution (50 ml) of the above-mentioned amino-alcohol (1.65 g, 6.59 mmol) was added active manganese dioxide (10 2 g) 10 times each in an amount divided into 10. After 2 minutes, the 10 reaction mixture was filtered with celite, and the residue was washed with dichloromethane (20 ml). The filtrate was concentrated to give an ynone compound (1.39 g, 85 %).
IIBO~ XNH2 lH NMR (250 MHz, CDCl3) ~ ppm: 1.54 (s, 6H), 1.78 (brs, 2H), 3.95 (s, 3H), 3.97 (s, 3H), 6.94 (d, J=8.4Hz, lH), 7.6~ (d, J=2.0Hz, lH), 7.81 (dd, J=8.3, l.9Hz, lH) .
Pale yellow oily state O O
25 UeO~\ X~H2 ~`~; X
llea~ CH=C(S02Ph) XNH2' HC ~
By using the above aminoynone compound (200 mg, 0.82 mmol) and sodium benzenesulfinate (160 mg, 0.82 mmol), a vinyl sulfone compound (21û mg, 66 96) was obtained in the same manner as in Example 20. This compound was dissolved in a .
2~ 7rd914 .
mixed solvent of diethyl ether (60 ml~ and ethyl acetate (20 ml), and the solution was stirred under nitrogen atmos-phere on an ice bath A 4 N hydrochloric acid-ethyl acetate solution (0.3 ml) was added dropwise thereto, and 5 the mixture: was stirred at the same temperature for 10 minutes. The produced precipitates were collected by filtration, dried and suspended in ethyl acetate-diethyl ether (1/5) . After stirring for :10 minutes, the precipi-tates were collected by filtration to give hydrochloride of 10 a desired vinyl sulfone compound (200 mg, 91 %) .
o ~{eO~ ~H=~(SO2~n~x}~H2 3~C
lH NMR (250 MHz, CDC13) ~ ppm: 1.90 (s, 6H), 3.86 (s, 3H), 3.94 (s, 3H), 6.95 (d, J=8.5H~, lH~, 7.41 to 7.60 (m, 5H), 8.02 (dd, J=8.3, l.9Hz, lH), 8.12 (dd, J=7.9, l.OHz, 2H), 9.19 (brs, 2H).
IR (KBr) cm 1 3407, 3227, 2841, 2037, 1658, I588, 1514, 1443, 1422, 1310, 1269, 117:3, 11a.6, 1080, 1019, 752, 632.
m.p. 149 to 151 C, yellow columnar c~ystal Example 30 O O
~leO ~J~ 0 ,~
MeO~ YEt 2 ~ ~ `C~l=C(C~Y)Cb!e2,YEt2 30 The ynone compound (200 mg, O . 66 mmol) obtained in Example 19 was dissolved in 10 ml of toluene, and while stirring the solution under nitrogen atmosphere on an ice water bath, a toluene solution (1.3 ml, 1.32 mmol) of 1.0 M
diethyl aluminum cyanide was added dropwise thereto. The 35 temperature of the mixture was raised to rooIrL temperature, and sti~ring was continued . Af ter disappearance of the ~ 21789~4 starting materials was confirmed, a 2 N sodium hydroxide aqueous solution was added to the mixture, and the mixture was extracted twice with each 2 0 ml of toluene . The residue obtained after the organic layer was washed with 5 water, dried (Na2~04) and concentrated was applied to silica gel column chromatography (chloroform: methanol =
30: 1) to give a cyano compound (20 mg, 9 %) from a desired fraction.
o LlcO ~
~ `CH=C(CN~CL!e2NEt2 UeO
NMR (250 MHz, CDCl3) ~i ppm: 1.11 (t, ~J=7.2Hz, 6H), 1.41 (s, 15 6~), 2.63 (q, J=7.1Hz, 4H), 3.94 (s, 3H), 3 97 (s, 3H), 6.92 (d, ~=8.4Hz, lH), 7.51 (dd, ~=8.3, l.9HZ, lH), 7.60 (s, 2H) .
m.p. 82 to 83 C, orange-tinted yellow plate crystal IR (Ksr) cm~l: 3424, 2969, 2824, 2214, 1660, 1597, 1582, 1518, 1426, 1273, 1157, 1020.
Example 31 YeO~XNEt 2 UeO~ CH=C(Clle2NEt~) N O
lleO
The ynone compound (500 mg, 1. 65 mmol) obtained in Example 19 and morpholine (150 mg, 1.65 mmol) were dissolved in 7 ml of methanol, and the mixture was stirred at room temper-ature overn~ght. After completion of the reaction, the residue obtained by concentrating the solvent under reduced pressure was applied to silica gel column chromatography 21 /89~4 ~n-hexane: ethyl acetate = 2: 1~ to give a desired compound (410 mg, 64 %) f~rom a desired fraction.
o 3~eO ~ e2~ ) N
UeO
H NMR (CDC13, 250 MHz) ~ ppm: 1.06 (t, .J=7.1Hz, 6H), 1.39 (s, 6H), 2.57 (q, J=7.2Hz, 4H), 3.76 to 3.82 (m, 8H), 3.92 (s, 3H), 3.94 (s, 3H), 5.86 (s, lH), 6.85 (d, J=8.3Hz, lH), 7.44 (dd, J=8.3, l.9Hz, lH), 7.53 (d, J=1.9Hz, lH) .
m.p. yellow oily substance IR (neat) cm~1: 3422, 2994, 2951, 2838, 2363, 1844, 1615, 1580~ 1505, 1462, 1410, 1390, 1362, 1260, 1204, 1154, 1125, 1026. : -Example 32 In the same manner as in Example 31, :~rom the ynone com-20 pound obtained in Example 19 and monomethylamine, a ~inylamine compound (yield: 95 %) o .Ue~ H=~ Ie2~1E~2~N~le was ~ obtained .
lH NMR (CDCl3, 250 MHz) ~ ppm: 1.09 (t, 7.1Hz, 6H), 1.38 (s, 6H), 2.57 (q, J=7.1Hz, 4H), 3.52 (d, J=5.2Hz, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 5.77 (s, lH), 6.85 (d, J=8 4Hz, lH), 7.42 (dd, J=8.3, 1.7Hz, lH), 7.52 (d, J=1.8Hz, lH) .
Colorless oily state IR (neat) cm~1: 2971, 2836, 2045, 1738, 1609, 1557, 1507, 35 146g, 1391, 1300,- 1211, 1175, 1144, 1026, 774 .
2~7~f~
.
Exampl e 3 3 ~--re C 0 ~ C O ~T ~I p n 1) Li~ Pr)~
~eO ~HQ O
I!eD ~1~
~OJ ` ~aNHPh ~ ~InO~ b{eO ~' 10 A tetrahydrofuran solution (100 ml) of propiolic acid ~5.64 g, 80 mmol) was stirred on an ice bath, and triethylamine (13 4 ml, 96 mnol), aniline (8.0 ml, 88 mmol) and phos-phorus oxychloride (8.2 ml, 88 mmol) wére added thereto.
The mixture was stirred at rool}L tempera~ure overnight, and to the reaction mixture was added water under ice cooling.
Under reduced pressure, the solvent was removed by evapora-tion, and the residue was extracted with ethyl acetate (50 ml x 2) After the extract was conce~trated, the residue was purlfied by silica gel column chromatography (develop-ing solution: chloroform/ethyl acetate = 2/1) to obtain an anilide compound (5.58 g, yield: 48 %~ Under nitrogen atmosphere, a tetrahydrofuran solution (40 ml) of the anilide compound (1. 60 g, ll . O mmol) was cooled to -70 C, and while stirring the solution, a 2 M lithium diisopropyl amide cyclohexane solution (11.6 ml, ~3 1 mmol) was slowly added dropwise thereto. After the mixture was stirred for 1 hour, 3,4-dimethoxybenzaldehyde (1.83 g, 11.0 mnol) was added to thereto.. The temperature of the reaction mixture was raised to room temperature over 1 hour, the mixture was 30 subseouently cooled to.O C, and then water (10 ml) was added thereto to terminate the reaction . Af ter the solvent was removed by evaporation under reduced pressure, water (30 ml) was added to the residue, and the product was extracted with ethyl acetate (50 ml). After the extract 35 was dried (anhydrous sodium sulfate) and concentrated, the r~sidue obtained was purified by silica gel column chroma-tography (developing solution: chloroform~e~hyl acetate =4/1) to give an alcohol compound (1.22 g, 36 %~ which was an adduct. This alcohol compound (1.20 g, 3.9 mmol) was subjected to an oxidation reaction by the same method as in 5 Exa~[ple 14, and the obtained crude product was applied to silica gel column chromatography (developing solution = n-hexane/chloroform/ethyl acetate = 1/1/1) and then rinsed with ether-hexane and collected by filtration to give the desired above-mentioned ketone compound (630 mg, yield: 53 10 ~).
H NMR (250 ~, CDCl3) ~ ppm: 3.93 and 3.97 (2s, 6H), 6.75 (d, J=8.5Hz, lH), 7.19 (t, ~J=7.6Xz, lH), 7.37 (m, 12H), 7.54 (d, .J-1.8Hz, lH), 7.60 (d, J=8 2Hz, 2H), 7.83 (dd, 3=1.9~ 8.5Hz, lH), 8.36 (brs, lH) .
Shape: pale orange powder m.p. 140 to 142 C
IR (K~3r) cm~1: 3324, 1680, 1630, 1599, 1584, 1545, 1510, 1462, 1442, 1420, 1321, 1271, 1171, 1144, 1020, 874, 760.
~eOx~ ~hSH G) ` CD~i~Ph ~ : ~
MeO~ CH=C (C01~'~Ph) SPh ~leO
~ CH= C (CONhPh) ~0 ?.(eO
35 The above ketone compound (200 mg, 0.65 mmol) was dissolved in 5 ml of dichloromethane, 70 ml (0 65 mmol) of thiophenol and one drop of piperidine were added dropwise thereto, and the mixture was stirred at room temperature overnight. The residue obtained after the solvent was concentrated was applied to silica gel column chromatography (n-hexane:
5 ethyl acetate = 4: 1) to give a sulfide compound (10 mg, 4 %) and an amine compound (30 mg, 12 %) from desired fractions .
Sul f ide compound C~{=C(CQhl~P~)~Ph ~D
lH NMR (25Q MHz, CDCl3) ~i ppm: 3.95 (s, 3H), 3.97 (s, 3H), 6.92 (d, J=8 2HZ, lH), 7.06 to 7.32 (m, 8H), 7.47 (d, J=7.0Hz, 2H), 7.58 (s, lH), 7.68 (d, J=9 8HZ, lH), 7.83 (brs, lH), 7.89 (s, lH) .
2 0 Amine con~nd O
~ C~l=C(~D~3~Ph)l;O
H NME~ (250 MHZ, CDC13) ~ ppm: 1.71 (brs, 6H), 4.33 (brs, 4H), 3.89 (s, 3H), 3.92 (s, 3H), 5.90 (s, lH), 6,84 (d, J=8 3HZ, lH), 7 13 ( t, J=7.4Hz, lH), 7.35 ( t, J=8.lHz, 2H), 7 47 to 7 . 54 (m, 3H), 7 . 65 (d, J=8 3Hz, 2H) IR (Ksr) cm~1: 3345, 2938, 1686~ 1599:, 1545, 1508, 1439, 1254, 1165, 1022, 870, 758 m.p. 196 to 198 'C, colorless needle crystal Exampl e 3 4 2~789~4 D
~o J~ PhSH
L~eO/~ ~ ~E' *
o ~le O J~ C ~S~h~ = C~CIIe2 NE ~ 2 lleO
o ~ h=c(sph)~e2~t2 l~e~
The ynone compound (500 mg, 1.65 mmol) obtained in Example 19, thiophenol (180 mg, 1.65 mmol) and a catalytic amount of piperidine were dissolved in 5 ml of ether, and the mixture was stirred under nitrogen atmosphere at room 20 temperature for 7 hours. After disappearance of the starting materials was confirmed, the residue given by concentrating the solvent was applied to silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain an ~x-sulfide compound (430 mg, 63 96) and a 3-sulfide com-pound (170 mg, 25 %) from desired fractions.
~-Sulfide compound o 3 0 ~ C (S~h) =~HCLle2 .~1E t 2 H NM~ (250 MHz, CDCl3) ~ ppm: 1.13 (t, J=7.1Hz, 6H), 1.48 ~s, 6H), 2.68 ~q, J=7.1Hz, 4H), 3.82 ~s, 3H), 3.93 ~s, 3H), 6.66 ~s~; lH), 6.78 ~d, J=8.5Hz, lH), 7.01 (s, 6H), 7.34 (d, J=8 . 5Hz, lH) .
.
!3-- Sul f ide compound ~leO~ c~ sph)~2N~l2 ~leO
H NMR (250 MHz, CDCl3) ~ ppm: 1 01 (t, J=7 1Hz, 6H), 1.44 (s, 6H), 2.56 (c, ~=7.1Hz, 4H), 3.89 (s, 3H), 3.91 (s, 3H~, 5.69 (s, ~H), 6.82 (d, ~J=8 2Hz, lH), 7 33 to 7.38 (m, SH), 7 57 (dd, ~=8 1, 1 7Hz, 2H) Exarnple 35 ~leO~ ~(~Ph)=C~lC~e~2NE12 ~$
lleD
o 2 t ~le~(SDPh~ C~e2NEt2 ~EC D
~0 T~le c~-sulfide compound (100 mg, 0 24 mmol) obtained in Example 34 was dissolved in 10 ml of chloro~orm, and while 25 stirring the solution on an ice water bath, 80 mg of mCPBA
(purity: 55 %) was added thereto The temperature of the mixture was ra~séd to room temperature, and stirring was continued for 2 hours After disappea~nce of the starting mater~als were c~nfirTn~rl, a saturated sodium hydrogen 30 carbonate agueous solution (0.24 mmol) was added to the mixture, and the mixture was extracted twice with each 20 ml of chloroform. The residue obtained by washing the organic layer with water, drying it (~a2S04) and concen-trating it was applied to sllica gel chromatography (n-35 hexane :- ethyl acetate = 2: 1) to give a sulfoxide com-pound (50 mg, 48 %).
~ 2l7~4 40 mg of the compound obtained here was dissolved in 10 ml of diethyl ether, a 4 N-hydrochloric acid ethyl acetate solution (O . 2 ml) was added dropwise thereto under nitrogen atmosphere on an ice bath, and the mixture was stirred at 5 the same temperature for lO minutes. The produced precipi-tates were collected by filtration, dried and suspended in ethyl acetate-diethyl ether (1/5) . After stirring for 10 minutes, the precipitates were collected by filtration to give hydrochloride of a desired sulfoxide (30 mg, 69 %).
IleO~(SOPh)=C~lC11e2~1Et2 HC~
lS1H NMR (250 MHz, CDCl3) ~ ppm: 1.21 to 1 76 (m, 12H), 3.23 to 3.86 (m, 4H), 4.02 (s, 3H), 4.06 (s, 3H), 7.05 (d, J=8 . ~Hz , lH), 7 . 57 to 7 . 75 (m, 6H), 8 . 01 (dd, J=8 . 5 , 2 . 0Hz , lH), 8.43 (s, lH), 10.49 (brs, lH) .
m.p. yellow oily state 20 IR (KBr) cm~1: 3409, 3003, 1649, l582, 1512, 1424, 1304, 1265, 1173, 1152, 1020, 984, 754.
Example 36 25 l~eO~ Cl~-C(SPh)C~(e2N~t2 l~eO
o lleO~il=C(~OPh) C~le2NEt 2 ~C ~?
I~eO
From the p-sulfide compound ~80 mg, O.19 mmol) obtained in 35 Example 38, hydrochloride of sulfoxide (60 mg, overall 2178q~4 yield: 68 ~) was obtained by the same method as in Example 35 .
o ~H=C(SDPh)CUr2~Et ~ HC
~1~0 lH ~MR (250 MHz, CDC13) ~ ppm: 1.51 to 1.84 (m, 12H), 2.96 to 3.22 (m, 2H), 3.42 to 3.54 (m, lH), 3.80 to 3.98 (m, lH), 3.97 (s, 3H), 4.00 (s, 3H), 7.08 (d, J=8.4Hz, lH), 7.52 to 7.61 (m, 3H), 7.76 (s, lH), 7.87 (dd, J=8.2Hz, 2H), 8.39 (d, J=8.4Hz, lH), 9.62 (s, 1H), 11.10 (brs, lH) .
m.p. 110 to 112 'C, colorless powder Br) cm~l: 3407, 2986, 1628, 1593, 1572, 1514, 1444, 1422, 1275, 1219, 1154, 1076, 1015, 872, 768.
Test example In order to evaluate the tyrosine kinase inhibiting activ-ity and the cancer cell growth inhibiting activity of the compound of the present invention, tests were carried out in a partially purified human EGF (epithelial cell growth factor) receptor tyrosine kinase activity measuring system and a cell culture system using human cancerous cells.
(Tyrosine kinase inhibiting activity) (Measurement method) The tyrosine kinase inhibiting activity was measured by using an EGF receptor which was partially purified from an A431 cell line derived from human squamous cell carcinoma and by improving the tyrosine kinase activity measurement method described in Linda J. Pike et al., Proceedings of the National Academy of Sciences af the U.S A. 79, 1443 ( 1982 ) .
-2 ~ 7~ ~ 4 The detailed method is as described below.
A431 cells were cultured in a Dulbecco modified Eagle's medium (DMEM) containing 10 % fetal calf serum ~FCS), at 37 5 C under 5 % carbonic acid gas. The cells were homogenized in a solution containing 10 mM N-2-hydroxyethylpiperazino-N~-2-ethanesulfonic acid (Hepes) buffer (pH 7.4), 0.25 M
saccharose and 0.1 mM EDTA and then centrifuged at 3000 g for 5 minutes. Further, a supernatant thereof was centri-fuged at 10000 x g for 30 minutes to obtain an A431 cell membrane fraction, and this fraction was provided for measurement as a partially purified EGF receptor which was an enzyme source 15 To a reaction mixture of the above-mentioned A431 cell rn~rn~r~nf~ fraction (10 to 15 ,ug), a 15 mM Hepes buffer (pH
7.7), 2 mM MnC12, 10 ~LM ZnS04, 50 IIM Na3V04 and a sample dissolved in dimethylsulfoxide (DMSO) (final concentration:
1 % DMSO) was added 100 ng of EGF, and then 75 ,ug of a 20 synthetic substrate RR-SRC peptide (a peptide described in Sequence ~o. 1) and 10 IIM gamma-32P-adenosine triphosphoric acid (55 5 Ksq) were added thereto to start a reaction.
The volume at that time was 60 ,ul.
The reaction was carried out in ice for 30 minutes, and the reaction was terminated by adding 6 ,ul of 10 mg/ml bovine serum albumin and 25 1ll of 20 % trichloroacetic acid. The reaction mixture was left to stand in ice for 30 minutes.
Next, after the mixture was centrifuged at 5000 x g for 2 minutes, 40 111 of the supernatant was sampled and adsorbed to P81 phosphocellulose paper.
35 This was dipped in a 30 % acetic acid solution for 15 minutes to fix, washed by dipping in a 15 % acetic acid solution for 15 minutes (washing was repeated four times) and measured the count of 32p attached to P81 phosphocel-lulose paper by a lis~uid s~-;nt;ll~tion counter, and this value was defined as A.
At the same time, the counts of a reaction in which the sample tested was not added and a reaction in which both the sample and EGF were not added were measured and were defined as B and C, respectively.
T~le tyrosine kinase inhibiting rate is det~rm; nl~l by the following Eormula.
Inhibiting rate ~96) = (B-A/B-C) x 100 From the inhibiting rate obtained by changing the addition concentration of the sample, an IC50 value (50 96 inhibiting concentration) was calculated.
20 (Cancer cell growth inhibiting activity) (Measurement method) Ks cells of human rhinopharyngeal cancer retain EGF
25 receptor on cellular surfaces thereof excessively.
By using these KB cells, investigation of the effect of a sample on growth of cultured cancer cells was carried out by the following method.
2 . 5 x 103 cell/wel of l~s cells were sowed on a 96 well dish and cultured in a DMEM: F12 (1: l) medium containing 10 96 FCS, 50 U~ml penicillin and 50 llg/mi oE streptomycin, under conditions of 37 C and 5 96 carbonic acid gas for 1 day.
35 Thereafter, a sample dissolved in DMSO was added to the medium (DMSO Einal concentration: <0.1 96) and cultured 2~7~q~4 under the above conditions for 3 days. The sample and the medium were replaced every 24 hours.
The count of the number of living cells was determined by 5 colorimetric quantitation at two wavelengths of 550 nm and 650 nm using a MTT reagent by referring to the measurement method described in Michael C. Alley et al, Cancer Research ~8, 589 (1988), and the value was defined as a.
10 At the same time, the count of the number of living cells when the sample was not added was also measured, and the value was def ined as b .
The cell growth inhibiting rate was de~,orm; n~ by the 15 following formula.
Inhibiting rate (%) = (b-a) /b x 100 From the inhibiting rate obtained by changing the addition 20 concentration of the sample, an IC50 value (50 % inhibiting concentration) was calculated.
The above results are shown in Table-2.
? 1 78 9 1 4 .
Table - 2 Tyrosine kinase Cancer cell growth Compound inhibiting activity inhibiting activ-(NO-) (ICso, ,UM) ity (ICso, ~
0.34 0.62 26 0.86 1.9 29 9 .4 3 . 9 97 8.2 2.6 335 27 . 9 3 . 1 278 1 . 7 0 . 95 2~3 1.1 0.23 350 1.4 0 57 3 52 0 . 47 0 . 63 349 5.8 2.0 29Q 5.0 0.83 327 27 . 3 5 . 0 253 ~ 38 0 . 42 Utilizability in industry The benzoylethylene derivative of the present invention has potent tyrosine kinase inhibiting activity and cancer cell ~rowth inhibiting activity, and the tyrosine kinase inhibitor of the present invention i5 useful as a carcino-10 static agent.
Sequence listing Sequence No: 1 Length of sequence: 13 15 Type of sequence: amino acid Topology: linear ~ind of seauence: pep~ide Sequence Arg Arg Leu Ile Glu Asp Ala Glu Tyr Ala Ala Arg Gly
Immunol., 1~ (9), 2965-2g71 (1991); Nature, ~, 253-255 (1992), etc.), inflammatiQn (Molecular Pharmacology, 37, 519-525 (1990); International Immunology, 4 (4), 447-453 (1992), etc. ) or the like. Thus, tyrosine kinase inhibitors are considered to be useful for treatment and 10 prevention of these -diseases.
Disclosure of the invention The present inventors have intensively studied to solve the 15 above problems ar,d as a result, they have :Eound that a benzoylethylene derivative with specific structure has potent tyrosine kinase inhibiting activity and cancer cell growth inhibiting activity nothing beyond this whereby they have accomplished the present invention. That is, the 20 summary of the present invention resides in a benzoylethyl-ene derivative represented by the following formula (I):
~ I
F~ ~ C O C :R ~ = C R ~ R
~3~
[wherein, in the above f ormula ( I ), Rl to F~5 each indepen-dently represent (1) a hydrogen atom, (2) -OR9 [wherein R9 30 represents a hydrogen atom or a C1-Cs alkyl group which may be substituted by a halogen atom or a phenyl group. ], (3) a halogen atom, (4) a Cl-Cs alkyl group which may be substi-tuted by a halogen atom, (5) -NR10~11 (wherein R10 and each independently represent a hydrogen atom, a phenyl 35 group, a C1-C5 alkyl group which may be substituted by a phenyl group, a benzoyl group or an acetyl group. ), (6) .
-SOpR12 (wherein p represenrcs 0, 1 or 2, and R12 represents a Cl-Cs alkyl group or a phenyl group. ), (7) a cyano group or (8) a nitro group, or~represent a Cl-C3 oxyalkylene group having 1 or 2 oxygen atoms by combining the adj acent substituents.
R6 and R7 each independently represent ~1) a hydrogen atom, (2) a cyano group, (3) a halogen atom, (4) a Cl-C5 alkyl group which may be substituted by a halogen atom, (5) -NR13R14 (wherein R13 and R14 each independently represent a hydrogen atom or a Cl-C5 alkyl group, or are combined together to form a C3-C6 alkylene group which may be inter-:
vened by -O- ) or (6) -SOC~R15 (wherein q represents 0, 1 or 2, and R15 represents a Cl-C5 alkyl group which may be substituted by a halogen atom, a thienyl group or a phenyl group which may be substituted by a halogen atom, a Cl-C5 alkyl group, a cyano group, a nitro group or a Cl-Cs alkoxy group. ) .
R8 represents (1) a cyano group, (2) -COR16 [wherein R16 represen~s a Cl-C5 alkoxy group which may be substi-tuted by a phenyl group, or -NR17R18 (wherein R17 and R18 each independently represent a hydrogen atom or a phenyl group which may be substituted by a halogen atom or a Cl-Cs alkyl group . ) ~ or (3 ) -CR22R23X {wherein R22 and R23 each independently represent a hydrogen atom or a Cl-Cs alkyl group, or are combined together to represent a C3-C6 alkyl-ene group which may be substituted by a Cl-C5 alkyl group, and x represents a hydroxyl group or -NR24R25 [wherein R24 and R25 each independently represent ~a) a hydrogen atom, (b) a phenyl group which may be substituted by a halogen atom or a~Cl-Cs alkyl group, (c) a Cl-Cs alkyl group which may be substituted by a phenyl group or a Cl-Cs alkylamino group, (d) a C3-C8 cycloalkyl group or- (e) -COR26 (wherein R26 represents a Cl-C5 alkyl group, a phenyl group or a Cl-Cs alkoxy group which may be substituted by a phenyl group 1, or are c~ombined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27--2 ~
(wherein 3~27 represents a hydrogen atom or a C1-Cs alkyl group. ), or a C3-C6 alkylene group which may be substituted by a C1-Cs alkyl group. ~ . ~ . Provided that when R6 and R7 represent hydrogen atoms simultaneously, R16 does not 5 represent _l~gl7R18 ~
or a salt thereof, or a tyrosine kinase inhibitor contain-ing the above benzoylethylene derivative or a salt thereof as an active ingredient.
10 In the :Eollowing, the present invention is; explained in detail The tyroslne kinase inhibitor of the present invention contains the benzoylethylene der_vative represented by the 15 above formula (I1 or a pharmaceutically acceptable salt thereof as an active ingredient. A5 the halogen atom defined in the formula (I), there may be mentioned, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., as the C1-Cs alkyl group, there may be men-20 tioned a methyl group, an ethyi group, a n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a neopentyl group, etc., and as the C1-C5 alkoxy group, there may be mentioned a methoxy group, an ethoxy group, a n-25 propoxy group, an iso-propoxy group, a n-butoxy group, an iso-butoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentyloxy group, a neopentyloxy group, etc As the C3-Cg cycloalkyl group, there may be mentioned a 30 cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group, and as the C1-Cs alkylamino group, there may be mentioned a methylamino group, an ethylamino group, a n-propylamino group, an iso-propylamino group, a n-butylamino 35 group, a tert-butylamino group, a n-pentylamino group, e~c.
2~7~4 As the Cl-C3 oxyalkylene group having 1 or 2 oxygen atoms, there may be mentioned -ocH2cH2-l -cH2ocH2-~ -CH2CH2O-, -OCH2O-, -OCH2CH2O-, etc., and as the C3-C6 alkylene group, t~lere may be mentioned -cH2cH2cH2-~ -cH2cH2cH2cH2 -CH2CH2CH2CH2CH2- and -cH2cH2cH2cH2cH2cH2-~
Among the compounds repre~ented by the above f ormula ( I ), preferred are compounds in which R8 is a cyano group or -CR22R23X {wherein R22 and R23 each independently represent 10 a hydrogen atom or a C1-Cs alkyl group, or are combined together to represent a C3-C6 alkylene group which may be substituted by a C1-Cs alkyl group, and X represents a hydroxyl group or -NR24R25 [wherein R24 and R25 each independently represent (a) a hydrogen atom, (b) a phenyl lS group which may be substituted by a halogen atom or a C1-Cs alkyl group' (c) a C1-Cs alkyl group which may be substituted by a phenyl group or a Cl-Cs alkylamino group, (d) a C3-Cg cycloalkyl group or (e) -COR26 (wherein R26 represents a Cl-Cs alkyl group, a phenyl group or a Cl-Cs 20 alkoxy group which may be substituted by a phenyl group. ), or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27- (wherein R27 represents a hydrogen atom or a C1-C5 alkyl group. ), or a C3-C6 alkyIene group which may be substituted by a Cl-Cs 25 alkyl group. ] . } . More preferred are compounds in which R7 is a hydrogen atom, a cyano group, a Cl-C5 alkyl group or -SOclRlS (wherein q represents 0, 1 or 2, and R1S represents a C1-C5 alkenyl group which may be substituted by a halogen atom, a thienyl group or a phenyl group which may be 30 substituted by a halogen atom, a C1-C5 alkyl group, a cyano group, a nitro group or a C1-C5 alkoxy group. ), and R8 is a cyano group or -CR22R23X {wherein R22 and R23 each independ-ently represent a hydrogen atom or a Cl-C5 alkyl group, or are combined together to represent a C3-C6 alkylene group 35 which may be substituted by a C1-C5 alkyl group, and X
repr-esents a hydroxyl group or -NR24R2S [wherein R24 and R25 2~789~
each independently represent (a) a hydrogen atom, (b~ a phenyl group which may be s~ubstituted by a halogen atom or a Cl-Cs alkyl group, ~c) a C1-Cs alkyl group which may be substituted by a phenyl group or a Cl-Cs alkylamino group, ~d) a C3-C8 cycloalkyl group or ~e) -CORZ6 ~wherein R26 represents a Cl-Cs alkyl group, a phenyl group or a C1-C5 alkoxy group which may be substituted by a phenyl group ), or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR21- ~wherein R27 Le~L~L~ ts a hydrogen atom or a Cl-Cs alkyl group. ), or a C3-C6 alkylene group which may be substituted by a Cl-C5 alkyl group. ] } .
Further, as a particularly preferred compound, there may be men~ioned compounds in which R1 and R5 are hydrogen atoms, R2, R3 and R4 each independently are a hydrogen atom or -OR9 (wherein R9 represents a Cl-Cs alkyl group. ), or R2 and R3 are combined to be Cl-C3 oxyalkylene having 1 or 2 oxygen atoms, R6 is a hydrogen atom or a C1-Cs alkyl group, 2D R7 is a hydrogen atom, a cyano ~roup, a C1-C5 alkyl group or ~SOq~R15 (wherein q~ ~L~ ts 2, and R15 represents a thienyl group or a phenyl group which may be substituted by a C1-C5 alkyl group or a nitro group. ), and R8 is a cyano group or -CR22 R23 X~ {wherein R22 and R23 each independ-ently represent a hydrogen atom or a Cl-C5 alkyl group, and x~ represents -NR24'R25' (wherein R24' and R25' each independently represent a C1-Cs alkyl group or are combined together to represent a c3-C6 alkylene group which may be substituted by a C1-Cs alkyl group. ) . ~ . Among them, more 3 0 preferred are compounds in which R1, R4 and RS are hydrogen atoms, R2 and R3 each independently are -OR9 (wherein R9 represents a C1-C5 alkyl group; ), R6 is a hydrogen atom, R7 is -~Oq ~ R15 ~wherein ~ ' represents 2 ~ _and R1S represents a phenyl group which may be substituted by a C1-Cs alkyl group or~ a nitro group. ), and R8 is -CR22 R23 X~ {wherein R22 and R23 each independently represent a C1-C5 alkyl ? ~ 7 ~
group, and X~ represents -NR24"R25" (wherein R24" and R25"
each independently represent a C1-Cs alkyl group. ) . } .
As the rLost preferred compound, there may be mentioned 5 compounds in which R1, R4 and R5 are hydrQgen atoms, R2 and R3 are methoxy groups, R6 is a hydrogen atom, R7 is a phenyl s ul f onyl gr oup, and R8 i s - C ( C~13 ) 2N ( C2Hs ) 2 -As a salt which can be formed by the benzoylethylene 10 derivative represented by the above formula (I), there maybe mentioned, for example, inorganic acid salts such as carbonate, bicarbonate, hydrochloride, sulfate, phosphate, etc., or salts of organic aclds such as formate, propionate, oxalate, fumarate, maleate, citrate, tartrate, 15 benzoate, phthalate, methanesulfonate, 4-toluenesulfonate, etc., and the like.
Further, the present compound can also form a hydrate.
20 In the following, preferred specific examples of the compound of the present invention are shown in Table-1.
R~ R C ~ CR~ = CF~7 R8 R~ s ~ ( I ) 217~914 g able-l ~1 0 ~\ ~ (R7)=C (2~ o Z3 1 ~ Rs Co;~-~urd R 1 ~ 7 2 3 R ~ R 7 ~o, =
H H H H H 'I H C,' r~ H H H H H H 1~ C0~7J~e 3 ~ H H H H H rl CO73u _ _ . _ . _ }il H H H H H H CO7BI~.
1-~ 2 ~e ~ ~ H H C.~l :~ H OH C.~l H -~i H H C~.' H OH H H H H c-r~
3 il H 03n H H H H C~
9 H H 0i1' H H ;l H C,.
10 H ~'e OH H H H H C.
1 I f~' .H C I H H H H C;~
17 H Cl Cl H H H H Cr' 13 H O.}!e Or.~ Cl i, H H C~
1~ H 0~2 OU2 B- ,! H H C~
1~ H O~!e Or.~e C~ H H ii CN
16 H ~le G~e NO2 H H 1I C~i 17 H 0'1 OH ~i ~02 I: H C~i -2 ~ 7~ 4 able-l (conLd) orl- 2- 23 R~ D~i ~ô 2 .
la H ~le ~H ~e H H H C."
19 H ~[e Q~e ~e .Y H li 5,~l ~0 H ~le O~fe e H H H CO-,~!e 7 I H ".e ~ le H H H 50~ 'e H 3 5H }~ H 'Ll H ca- ~
73 3 OH 51i H 1~ H r CO 4 D3(e OH H H H H CO.-,Ye 75 ~ 'e O~n .~ H H H CO-,~I~
76.~ e D~e ~ H H X CO.,~e 77 U ~ 0~'~ C I 11 7rt H ca-~e 23 ~- 04~e Q re 3r H H H CD~e ~ H H Q3~e H H P R CO.~e 30 H --D5~70-- X H 11 Ir; CO~. e 31 H H -l~e2 H H e H ~C~e 37IY H -~l2 H H .~' H CO~e 33 h H S~e H H H H C02~e 3~ H DUe O~le C~ rl h H ~5-,~e 35,~ We QYe CFS H ~ H U1~'1e 36 ~ O~e O.''e CFS NO~ H ~I CO~'e .
37.~ O~e O!le NO2 r' 'i H CD^,l!e 3a H C~e Q!le ~0~ rl Ca ~L!e ~ ~ 7~
Tabl~-l (contd) com- R ' ~2 R3 ~ ~ R-- 7 6 ~ 8 N~ . .. ..
3S H 5f~e Cl H H 'r' H C0-,.~fe ~0 il Cl G~ H fi H h CO,~fe 1li C I C ! C I rf H H CO-,~fz ~ ~ ~I C I Ol~e C ~ H H H CO ,l~e d3 R 5l O.~i Ci It ~I X CO ,~.e h' ~e OH l{e H H H CO~,e S h l!.e O~ e ~i~e H h' H CO~d-e .
fi' ~i'e Of~fe ~e H H H CO7nSu ~7 H O~le O~e ~le H H H CO~Su 8 H H OH ~e H H H W7n3u ~9 H H Olfe f~.'e H H h C0~;~3u , ~0 L; h C! ~fe H H H W7r'~u S! H OH OH ~fe H H H W7nSu ~2 ~1 01`~ OH .'.fe H 1~ H C07S r 53 li OlJr OH ~.e H H H CO~
H O.~fe Oen rlf2 H H H C023r ~5 H H 03n l.fe h H h' Cf~-,3r ;3~ H H O~le .~e 'l H h C073r 57 I H C I .~le H 11 H co7e ~
58 H Cl Cl ~e '.~ C07hr ~9 r' C ~ C I 'I H ~ C07~ r 2i78~4 Ta~ 1 (contd~
poLlmnd R ~ 3 R ~ ; R i' .~ 7 r~
NO .
6~ ~. C I r e C I ~{ X H C023r 6I R L~fe D~e h H H H ~ i.'f~
67 L f1 Q~le ,L ,L, R H ~ 2 ~i3 h i C~ H IL.' H H ~ ,?~ff7 H H 03n H LLI ~ '~f < "~H7 6âh' OH OH H H Ll H ~ f:fH7 6~ .H OH L~H H L' X H ~,~i~f~e Dt H G~e O'f ~f 'rf H H ~h'^' 60 ~ H H H H L! 5~h~e 6g H L; ~le H ~f H H 5 ~iY,~'e îO L ~ Cl H H H H 5~?f.L~fe 7I R H ~3n H H E~' H ~,~
77 ~ H D3n h H H H ~`f~L2 t3 If ~l a~e H H H H ,~ ?fE t2 H O~e D~e H H H H ~ ?fE t 2 7:~ H ~.!e 03n H H H H ~,~iEt2 ~ -- .
t6 H ~, OH H H H H ~ ~ L 2 ~t II '~ Orf H H H ~f ~/ ~IEt~
î 8 ,( H C I ~f H H H ~ f~E ~ 2 tg H Cl Cl H ~l ,f H , I-~Fl~
30 ~; C ! ~!4e C l H H H ~ N~ L 2 23789~
Table-1 ( contd) Co~n- Rl R7 R3 R~ R~ R6 ~7 R8 No .
. .... .
8I IH' O~!e 0Ue C! H H H ~N~I~
., 82 8 0.U_ ~e CP3 8 H H ~i~
83 H Dlle D~e ~e i.~ H H ,.
B~ h' O~e ''~e S~fe H H H ,N' Pr~
8~; H 0~e ~.Ze CF3 H H H ~,ii! Pr 7 8b H ~ie 13Ue H l~ H H ,tZiPr7 &~ H H We H ~ ~, H ~,~ii Pr2 88 H H ~3n I~ H H H ~,ii! ?r 7 H H Cl ~ H H H ~Pr5 90 H H H .~ H H H ,;liiPr7 91 H O~'e 5~3n H H H H ~ pr7 57 H 011e 5~ H H H H ~C~?~ip~7 93 H O~e OH Cl H H R ,~hi?r7 9~. pl O~e ~H C I ~{ H H ~ N~>
9a H Oil.e 0' 'e C I H H H
96 H ~ O~e ? r H H H
97 H O~'e O~le H H .'i H
98 H H 0!~'e H H H H >~ 'I,~) g3 H H C I H H H ~l >~ li--) 7 ~I H Y H ~ N~
IOL H H O~n H H ,~
-217~14 Ta~le-1 (contd) - , r ~ _ C:om- R! R2 7~.f R-i ~ S RS R~ Rc No !0~ 3 H H h H y .
lD3 Ll D! H Cl H h' H >C~ li~
lOi :1l H ~ H H X H >C~ ~i'7 lD~ ;l H Slle H h X H ~
106 p; lu -Nl'~2 H H X H ~ ~if~) 11)~ ,{ -OCI;lsO~ H H H H ~ ~f~--) 138 H H ~ ~F2 H H H X
109 ~ O~i~ Ol~h~2 H H h' H
-~ 7 110 H OL~ O~e 1l H 1 H I ~
~t~
111 H H G~e H H H H \l--die , ~12 H GH 0!~ H ~ ~ H I ~
~-_;7 3 H H Cl H H H ~e ~N~[7 I! ' H H H ~ H Hl h .
H H rl ~1 ' I H' X ~ ; 7 ~ 217~914 Table-l ( corLtd~
com- R l ~12 F~ 3 ~ 6 ~ ~ R
No . _ .
1'~6 }! h Ohe t; H x~ z 111 ~ Dl~- Oble h H 1~ tl X~~2 113 H D~le 53n H H h' X~ç~2 ~#ET 2 11 H Dh'e D~n H H H H /~
~.~
1?0 h' D.''e nJ~le H H H H
~E.7 1~1 H 1:1 ~e H H H H ><
~C~7 !?7 H H ~! IA H H H
. . . .
~ 2 173 .; h H H H H
~ ~2 12A H DH OH H H H H /~
125 H OH D,l H H
!76 :i We 011 ~ I h' --217891~
Table-1 ~co~td~
com-p~ D~} R7 R3 R4 D-, R ~ / R3 No .
. . .
~2t~
L~7 t. ~ke G~2 ~ H ~, H
~13 t ~1 1~3 H H Lf2 h H H H ~Xr ~E
179 h t~ C 1 H t H H ~><r !3~ H H C I H H H ' ~
131 H R Oif2 H H H H \, N~>
= .
137 H D.~e D.L'e H H H H >~
133 H L4~ 0~-12 H H H H ~>
I ~ H O~'e G~!2 C I H H H \~ ~
.
H Dl~2 C~e ~ r tt 1I H >~
~6 n 0.4e O~!e Ct'3 H H H
~ ~ ~ 7~
~able-1.. (cont~d com-~nd p~ 2 R3 2~ ~s ~ R~ 28 No .
137 H ~e 53~e S02Ue ~ H H ~N~>
138 H 0~e ~le ~e H H H >~
l~g H O~e {dfe ~'Oq ~ H H
11 0 ' ' C~ 4e H NO 2 H ~ ~N~>
. .
OH aH H H H ~ ~N~>
1-7 H H O~ H H H X ~) H ~3~n H H H h' lAA ~ H H H H H H >~
H-OCHza- H ~I H ~[
1 A 9 H C; G~ C I ~i H ~ ?
2~89~
able-l ~ contd) Co~
d R ! 2 ~ p~ 3 R ~ 7 ~ 8 No .
Cl i~ Cl h H H
e _~ H Cl !l Cl H H ~ O
.YE
1~9 H -H 13~ C! H H H ~S
:~0 .'J H ~'e H H h' \,.i~Et2 ~,~I,-t2 a~lD O~le h H ~ H ~
'~12 1~2 H Qljo OH H H H H ~j 1:53 ,:f H OH .~ H H ~Y
~?lf~t,, 15~ ,~ H Cl H H H H O
~N~t2 155 H H rl .~ H H H
156 H ~' H H 1,' H 'I ~N~
~1~8~4 Ta~le-1 ~co~td) -c~)m-pOUD~ ~I B~ R3 R4 Rs R R~ R~
N
157 il H O:~e H H ;,! h' 1~8 H ~e Dile H H H 1' ~;
1~ H ~le 03n i~ H h' '1 1~0 '' H Cl H H ;~ H
161 H H 03n ~ h H H
h' -DCH20- H h H H
16a H -D~P.20- H H 'H H
16' H C.e O~e H ,~ H ~,~
16~ H OH OH H H h H ~ r~>
!65 H H OH h t! H tl ~
2 1 7~9 3 ~
Table-l ~ co~t~L) com- e1 ?- ~3 R 1 ?~ ~ R-o F~ 8 ~lo .
rl C I H H H H ~N~>
168 '~ R 1~ i{ h ~{ H
, ~
Ir~3 ff ~ H H h' li H ~5 2 ~ ~EL7 170 'r; H O~!e ~ H
171 ~ O~e 1~ R H H l, ~2 77 Irl [~J'e 0~ H h H ~ EL2 t 7 173 H H DB~ H H ~ 3 2~
,~ {IE t 7 lîg ~ H Cl H H H H 2S
!7~ h' H Cl ~ H H H ~E~2 176 H H G~e ~ rl ~ ~flE~2 . .
21f89~4 Ta~le- 1 ( contd) com- E' R7 ~ R' R~ , E~ ?~a .
177 H O.!e Q~.e H i1 H H
~3L~
5 Off Of~ H r! H H ~
79 H H OH H H f' ~5 L2 ~ f~E~2 H H H H H :~ ff 181 H H H H f5 CY H C~
1~ :Y iY D~le H .Y C~ H CN
H ~e O.~le H H CN ~5 CU
1~ H OH OH H H C,Y H C~
If3;S H H H H fl C~Y ;H Ct5 106 H H 05~il H H CN H CN
8 I H H C I H H C,V H C~l ~8 H H C I H H SO2Ph H C[Y
1a9 H H 0.5.~e H H SO~Ph H C;~
!90 .~ G~e Ol,le i'. H SO2Ph , C, 191 H O~Ue OH ~I H SO7Ph H C~
19~ f5' G5~e o5~n H H SO7Ph H C~', !93 H ~,5~e O'~e H n S?n H C,~l ~ 2~7~9~
Tabl e-l ( c~ntd) c ~ 2 R3 p~ p~; p~ ~7 R~
NO
19~ ~' Ol~e Qlfe H H Cr ~ R C~
lSa j1' G~le O~e { '~ ~F3 ~ CN
1~ H Ole Q~e H H SOPh H C.~l 197 11 l~ Q~le R H SOPh H C}i lS8 H H ~Xle .H' H SOPh R GO2~e 199 H ~e OL(e H R SO~h H ~e 2Do :~ Q'~ QH H H SO~.~ H C02~e 201 i~ H OH n 1~' SOPr H CQ2;~e 207 H L71l2 O~e !1 H ~ ~' CG2 ~e 203 H R .1 R H ~(e H CQ~L'e . _ ... .
70~ R~ i~,! ~e H H SO2Ph H CO~lle 2~5 H C~!e D~!e H H SPh H CG2Lfe 2~S H Ol-le G.L~e H h SQ~e H CQ~Le 701 H H C l H H S02~e ~ CO2"e 20S H ~: C I H }~! SO211e H CO~Bn 209 H H Q~e '~ H S02Ye H C023n 210 h D~e Q~e H H 502P~. H CO28~
211 'I G~le We H H .~le H -CO'~ Ph Z12 H 'I ~I H H '!e ~ -CQ~ Ph 2!~ H H C I H H ~le ~l -CO~ iPn ~ .
? 1 7~891~
Table-1 (contd) com-Rl RZ ~3 R4 Rs R6 R~ R
No .
.
2!~ H H C! Y' H CN H -COr3H~CI
, 7!~ H ~!r Dile H ,~ CN H -CD~.~Cl ~16 H ~le O~'e H H C,Y H ~
. . , ~1 ~17 H G~'e Oble ~ H CN H -WYH~
71g ~ le O~!e H H ' -N~ -CG.i~Y:'h .
71S H ~'e ~e 1~' h' '`O~'e H -æ~ H O~le O~le h' H SO2Ph H -~HP~
771 Y H ~le H H S~2Ph H -C~-X?
777 H H C l H H S[32Ph H -CG~Ph ~3 H -~H~CHz- H H S02Ph h -C~ iHPh 2~ H D~le C~[e H H H SPh -CO'i~Ph 7?5 H Ql~e D~!e H H H H ~I~P~2 776 H D~'e 5~(e H H C,l ~ t 7~7 H fl O.''e H H C.'~ rl ~ ~ ~ 2 ~2a H ~i C ! H rl C~ H ~ ~ 2 . .
2 1 789 ~ 4 Ta3~le-1 (contd) _ _ .
com- I ~ 2 R ~ R 4 ~ 7 p~ 8 No .
~2~ H H OgD -il H CY ` ti~2 230 H H D3n ~ ~ Sû7Pn H ~t2 ~31 H ~e l~le H H SD-~Ph H ~~.~t2 a~'e al~!e H H SD~le H ~t2 ~33 H Q~le ~le H H SQ2CF3 H 5~i~1~.2 234 ~ e ~lo H H S02CF3 H
~35 H ~.;e O.,le H H Sa~h H r~3 ~3~ H H aLf.e H H SD2Ph H ~ N~--) 731 H H Cl H H S02Pnh H N~>
738 'H H H H H SO~Pb H
~39 H D~e ~1~ l~ H C~l H .i'~>
~0 H H Q~e H H CN H i{--) ~! H H ~gn H H C~i H '~
7 " H ~gr~ H H SOPh H
~3 H H ~e H H SO?h 7~ H O.i[e O~!e H l! SOPh H ~ r,'~
r1~t 2 245 H O~e Ol.l:e H H SOPh H X
' ~t ~!6 H Ol'e We 1~ ~I CN 2 2 1 7~9 ~ ~
~able-1 (Co Com- ~I R7 ~:~ P`~ ~5 R6 a7 R~
N~
l, H Qi.fe H H ~ ?3. L7 ~8 H H ~ C~ L, ~9 ~1 H I~Dn H k C^. ' r3! ~A 7 _~ ~t~
~50 H H 53 n 3~ H SOFI~ H
~t~
2 I H H SOPD H ~ A
'i H ~ e H H C~3Ph c ~3~ t 7 ~3 H H H H H ~e ~12 -Ca~lPh --~ 7 H ~e ~le H H 50733~ H X
H H 01~e H H Sa73.'h ,\ .~nL 7 . f~ h~
~6 H -~CH~?O- H H Sl37Ph H >
_ _~ t~l3, L
~57 H ~ C I 'I 'I SO7Ph H A
2~8ql~
T2ble-l (co~td) com- Rl R~ R~ R- R~; ~ô R~ R~
No .
2a3 .HI li H H H 507?h H f->~ t 7 2a~ H ~ H H St~_h h ~><
2EO H O?le Qlle H H 507"e ~ t 7 201 H H 0~2 H H ~O,Ye H ~i ~S2 H H O.~'e ~ H
~63 H O~!e ~ e h H ~;e J~ R
2~ H Q~ DH !,, H Ue ,>~h3 t .
26~ H IY OH H H ~e H S<
266 H ~[ Qs~ H H ~t H J><
2~7 H ~.~le O.Ye '~ H Et ~l _'~i~'Et2 217~14 T2~ble-1 ( cr~ntr~
COL~_ R 1 R 2 R 3 R ~ R :' R ~ R ~ R o NO .
2~8 H G31e O~e H H SDn H ~< -2D~ Ir 0~1~2 O~e 1~ h' H 53h '~< 2 .
' ~E7 ~:~0 H H 03~ H H H ~i~h '><
~ ~t~ I
~71 H q O?r!e H H H S4'2 ~\~ 2 ~L7 ~7~ H a~2 0~'2 H H H ~{e ~<
. =
273 H O?IE G~- H H H S~:elie ~ t 2 = =
H H G~le H ~ H S~2~e ~ 2 - ~t2 ~75 H H C I H H H S02ilz ~><
t ~76 H H h H ~ q S~2Y2 '\~<
f~ ~iE;t2 2T7 ~,' H H r( ~ I SO2P~ ~
2 1 ~
Table-1 ( contd) Com- Rl ~7 R3 R' Rs R~ R~ R-No .
~iEI 2 273 ~ Olle al~e H H H SO2Ph '><
~7a H y n~e H ~I H ~O~Ph ~<
- h~7 730 H H DBr~ H H H ~O~Ph X
2~1 H H Cl H H H S07Ph ~/\~ 2 737 b Cl Olle C~ H H SO2P}l ~'\/ 7 si~t 2 ~83 H O~e O~e C I H H sa2P~ ~\~
_,~ h~7t 7 2~4 H D~[e D~le Br H k ~`07Ph X
t 7 HQ:~e a~e cr 3 I H S07Ph X
2;~6 H O~e O~e N02 H H f~E.z 2~7 H a.'~ Je H tl ~ t 2 2 ~ 7~91 ~
~a~le-1 ( ccmtd~
com- Rl R2 R ' R- R~ R'3 F~7 R3 ~io .
OCH7Q- H H H 502P'~
~9 H --DC~zO - H ~0 2 ~ 5~2Ph ~< N~
790 H --O~H20- O'~e h' H S''.,Ph ,5<N~
29i H O?~e G~!e O~e H H S02r;~
2~2 H C I C I H H H SG-,Ph 29.~ le O~le H H -H SO2~4c '\~
29- H ~e OJ,.~ H H H SG2~ C I ~
~95 H OLle Ol~!e H H H 503h ~?~ 2 9~ H 0~1 G~!e H ~I CP 3 SOD~ ?E 2 ~ tiE L
297 H Olle O!le H H ~ CP3 X
79~ ~, OlJe OU~ H H H P ~E~2 2 ~ 7S~,9 ~ 4 Ta}~le-1 ~contdl p~ ~ I R7 R~ R~ R~ ~ R ~ ~c No .
æ~s x D~le ~{2 'H H H SD~,Ph ~/ #~>
3DO H H Olle H X H S02Ph ~/~
3~1 H ~ C 1- ~I H H SO zPh 30~ H H 0~ H H H SO7Ph x~
303 H H 03n H H ~ie SG?Pn 3C~ H 031e ~le H H C" 53~Pn ~,~
3a5 H ~e ~e H H SOPh SO7PI' ~ 'i~) 3~S H Q~l= O"e H H 53~Ph 507Ph ~/ '~
307 H Ol~e Q~e H H SO-~le SO7Ph ~/'~
3~8 H O.',!e Dl~e 'I ~ SO7~e SO 7~Ue ~/ rl;O
-9~4 ~a~le-1 (contd) com- R7 R3 R~ R~; R2 ~ ' R~3 No .
309 H D~e ~e o h' H S0 ~f6 ,< ~
310 X OHe D e H ll CN So~ e~5~t~) 3l1 H a~l0 ~e ' H ble S0 ~-~e 31~ N &,~e D~le H H H SO~,3 313 .~ a3l ~le h H H Sû~e 314 H Oh'2 D~e H H H S~-'le ~N~
315 H H ~e H H H SO-,~e ~/ ~`'~
3!6 H H Cl H H SD7~!e 3!7 H H C l H H H C~
318 H OVa O~le ~ H I C~
2~7~91~
Table-1 (coIltd) com-polh~d R ! R~ ~3 R~ R~ P~ R7 R~
~o 31S 11 Q~e Odle H H H r ~S<~
3~û H ~!e OYe H H H Sl~3 ,<r.~) 371 H H O~(e H H H S~:e ~27 H H Cl ~ H H SPl ~5<h'~
~3 H H Cl H ~ H SPh ~
32~ b H Ot~l_ H H H SPr ~.ri~) ~75 H H Qqe H H SOPn H
326 H H OYe H H âOl'h H ~S<`
327 H OY.e C~fe H H H âO2Ph ~t~
~28 H ~t!e rl~e t( H t~ â~Ph 'S< ?lH2 217~ql~
~able- 1 ( corl td ) . ~ ~ .
pOU~ p ! R7 p~3 p~ ~ R6 ~ R8 NO .
3~5 H GMe ~ H H H SPh ~iliPr7 330 H H JMe H ~I H SPh ~,~lip{7 331 H H C~ H H H SFh ~ r7 33~ H H Cl H H H SGPh ~,.~i?r2 333 .~ H D?~e ~ H H SOPh ~I~!pr7 33~ H Q~le ~'.~ H H H SOP~I ~, NiP~ 7 33~ H ~!2 0~(e H H H SO7Ph ~ Pr~
336 H H f.~e H ~ H S02PA ~3Pr2 337 H H Cl ï r H S02Ph ~lip,7 338 ~I H Cl ~ H C;~ H ~ NiPf7 2 ~ ~$~ 1~
3a, Table-1 ( corLtd) co - R " ~ 3 ~ 4 R ~ ; 8 No .
33g X C~'.{e O~le h' H CN H ~iPr, 34D H ~e O~e ~I H CN H ~,iliPr2 3~1 H DUe O~e H H 502Ph H ~,NiPr2 .
34~ H O.;~e Q~ H ~!e H --,ip 3~3 H O~e ~e H h' H .U~ ip}2 3A~A H O~e ~e H H H 1~ ~13h~Ph 34:~ H H H H H H ~:e i~0.~3Ph 346 H H H H H 11 ~le CO~e N~
3A7 H 0!~ ~Ye H H H -h'~:~Ae 342 ~i Ollc O~le ~I r( H - ~
2~7~
Table-1 (co~td) com- R~ R~ R R~ R8 No .
3~3 H OUe O~te H H H Cii ~,/Nr~l2 3a~ H. OUe O~le H H H 50 ~10 ~< U~ t _ _ 351 H ~:[ il~^ i{ IH H -SOA~ille ~
. 357 H 0,!l2 a~l2 H u I -S~~~ ,5<N~-2 The compound of the present invention represented by the above fo~mula (I) can be prepared through, for exa}3ple, the following route.
20 1 ) H~ R8~
R I ~l R ! OIH
p 2 ~ C~:10 U----R 3 (r~/ ) R2~ --t ~ ~ Al=L i ~ ~(g ~ = R 4 h~logen CtO.~. .la ( V ) tl C;~
R I 0 or RSH
a 3~ o r ~ S 2 tl R ~ la. k, Cu.
P~2A t (p~=~lkyl) ( lTr ) 3 5 ( Scheme 1 ) 27 7~q~4 ~wherein R1, R2, R3, R4, RS and R8 are as already defined. ) For example, by reacting the metal acetylide represented by the formula (IV) which can be prepared by making a base of 5 an organometallic compound such as butyl lithium, ethyl magnesium bromide, etc., a metal alcoholate such as sodium methoxid~ etc., a metal hydride such as sodium hydride, potassium hydride, etc. or the like act on the acetylene derivative represented by the above fDrmula (III) in a 10 suitable solvent including an ether such as tetrahydro-furan, diethyl ether, etc., a hydrocarbon such as benzene, toluene, etc ., a protonic polar solvent such as methanol , ethanol , etc ., an aprotic polar solvent such as dimet~yl-sulfoxider dimethylformamide, etc. or the like at a temper-ature of -100 C to +100 C for 5 m~nutes to 12 hours, with the benzaldehyde derivative represented by the formula (II) at a temperature Df -100 C to +100 C, preferably at a temperature of -30 C to ~50 C for 5 minutes to 24 hours, pref erably f or 3 0 minutes to 12 hours, the adduct repre-20 sentea by the formula (V) can be prepared. sy oxidizing the compound (V) in a suitable solvent, fQr example, in a hydrocarbon such as benzene, toluene, etc., in a polar solvent such as acetone, wacer, etc., in a halogenated hydrocarbon such as dichloromethane, chloroform, etc. or 25 the like, the compound of the formula (I) can be prepared As an oxidizer, there may be mentioned, for example, a metal oxidizer such as manganese dioxide, chromic acid, etc., and an organic oxidizer such as oxalyl chloride-trifluoroacetic acid anhydride, etc. Further, for example, 30 by subjecting the compound (V) to a hydrogen transfer reactiDn using aluminum isopropoxide or zirconium chloride in a carbonyl compound such as acetone, cyclohexane, etc., the compound (VI) can be also prepared.
2 ~ 789 ~ 4 Rl Rl R 2~ C O? ~ R ~ C 0 X ( VI ) 5 R4 R4 (1¢), P~(O}.C~
(~) (~) ( Scheme 2 ) (wherein R1, R2, R3, R4 and R5 are as already defined, ) Further, for example, as shown in the above Scheme 2, by reacting the acid halide compound (VIII) obtained by reacting the benzoic acid derivative represented by the 15 formula (VII) with thionyl chloride, phosphorus penta-chloride or the like in a hydrocarbon type solvent such as benzene, toluene, etc. or a halogenated hydrocarbon such as dichloromethane, chloroform, etc., with the compound (IV) in an ether such as tetrahydrofuran, diethyl ether, etc., a 20 hydroGarbon such as benzene, toluene, etc. or a mixed solvent thereof at a temperature of -100 C to +100 C for 5 minutes to 24 hours, the compound (VI ) can be prepared .
Further, for example, by reacting the compound (VIII) with the compound (III) in the presence of catalystic amounts o~
25 a palladium complex and a copper (I) compound in a suitable solvent such as tetrahydrofuran, benzene, etc. at a temper-ature of +10 C to +100 C for 30 minutes to 48 hours, the compound (VI) can be prepared.
30 By reacting the compound (VI) with a 0.5 to 10 e~[uivalent amount of a metal cyanide such as sodium cyanide, potassium cyanide, copper (I) cyanide, dialkyl aluminum cyanide, etc.
in an alcohol such as ethanol, etc., a hydrocarbon such as hexane, toluene, etc., an ether such as diethyl ether, 35 tetrahydrofuran, etc., a polar solvent such as acetone, water, etc. or a mixed solvent thereof at -70 C to +200 C
.
for 0 5 to 48 hours, a compound in which R6 or R7 is repre-sented by CN among the compounds of (I ) can be prepared .
Further, for example, by reacting the compound (VI) with an 5 amine represented by the following formula (IX):
HNR13R14 (IX) (wherein R13 and R14 are as defined in the formula (I) ) 10 in a polar solvent such as water, methanol, ethanol, etc., in a suitable solvent such as benzene, acetone, dimethyl-sulfoxide, etc. or in a mixed solvent thereof at 0 C to 150 -C for 5 minutes to 48 hours, a compound in which R6 or R7 is represented by -NR13R14 (wherein~ R13 and R14 are as 15 already defined) among the compounds of the formula (I) can be prepared.
Further, for e~ample, when the compound (VI) is reacted with a sulfur-containing compound represented by the 20 following formula (X~ or (XI):
RlSSH (X) R1SSO2H (XI) 25 (wherein R15 is as defined in the formula (I) ) in a suitable solvent such as water, ethanol, benzene, acetone, dimethylsulfoxide, etc. at -20 C to 150 C, a compound of the formula (I) in which R6 or R7 is repre-sented by SOlR15 (wherein l represents 0 or 2, and R15 is 30 as defined in the formula (I) ) can be prepared. In place of the compound represented by the formula (XI), a salt such as correspol'iding sodium salt, lithium salt or the like may be used depending on stability thereof, or the reaction may be carried out while generating the compound (XI) in 35 the reac~ion system by adding an ec~u~v-alent amount of 2n acid such as acetic acid, hydrochloric acid, etc. to the sal t ? ~ ~7~ f ~
sy reacting a compound of the formula (I) in which R6 or R7 is represented by SR15 (wherein R15 is as defined in the above formula (I) ) with an inorganic oxidizer such as chromic acid, selenium dioxide, sodium metaperiodate, etc., 5 a peracid such as m-chloroperbenzoic acid, hydrogen per-oxide, peracetic acid, etc., a halogen such as iodine, bromine, etc. or the like in a halogenated hydrocarbon such as dichloromethane, chloroform, etc. -or a polar solvent such as water, acetic acidr methanol, etc. at -20 C to 100 lO C, a compound of the above formula (I) in which R6 or R7 is ~SOmR15 (wherein m represents 1 or 2, and R15 is as defined in the formula (I) ) can be prepared.
Further, for example, by reacting the compound represented 15 by the formula (VI) with a C1-Cs alkyl copper complex prepared from a 0.5 to 5 equivalent amount of c~opper (I) iodide or copper -(I) bromide and a 0.5 to 10 equivalent amount of an organic lithium or oryanic magnesium compound such as C1-Cs alkyl lithium, C1-Cs alkyl magnesium bromide, 20 etc_ in a suitable solvent such as diethyl ether, tetra-hydrofuran, etc. at -lO0 ~ to +100 C for 5 minutes to 24 hours, a co~pound of the formula (I) in which R6 or R7 is represented by a C1-Cs alkyl group can be prepared.
25 Further, for example, by, if necessary, after deprotection, oxidizing the following compound (XII) which can be pre-paréd by reacting the compound (V) or a compound obtained by protecting the hydroxv group of the compound (V) by a suitable protective group, with (X), (XI) or the alkyl 30 copper complex which are the above compounds in a suitable solvent such as water, etbanol, tetrahydrofuran, benzene, dimethylsulfoxide, etc. at -100 C to +200 C for 5 minutes to 48 hours, a compound of the formula (I) in which R6 or R7 is represented by a hydrogen atom can be prepared 35 (Scheme 3).
2~9~
.
7 R I ~R7a ~ C (~?3 )=I~:~.R
ProteCtior of hydro~ group ) or or 10 - Cl-C5 alkyl co~per con~plex 2 R I oR
R ~X=0R~s R~
2 I Rs R~
1 ~ Deprotec_ ) ~- - , r I ) ~) Oxidation (Scheme 3) (wherein Rl, R2, R3, R4, R5 and Ra are as already defined, R28 represents a hydrogen atom, a 1-ethoxyethyl group, a tetrahydropyranyl group, a dimethyl-tert-butylsilyl group, etc , R29 represents SOlR15 (wherein l represents 0 or 2, 25 and Rl5 represents already defined one. ) As the protective group, there may be mentioned a 1-ethoxy-ethyl group, a tetrahydropyranyl group, a dimethyl-tert-butylsilyl group, a benzyl group, etc., and as the oxida-30 tion conditions, the oxidation conditions from the compound(V) to (VI) used in Scheme 1 can be used.
Further, for example, when a compound of the formula (V) in which R8 is represented by ~7~
.
N~?30 ~3 ~ 73 5 [wherein R22 and R23 are as defined in the formula (I), and R30 and R31 each independently represent a hydrogen atom, a C1 to Cs alkyl group which may be substituted by a phenyl group or a Ci to C5 alkylamino group, a phenyl group which may be substituted by a halogen atom or a C1 to Cs alkyl 10 group or a C3 to Cg cycloalkyl group, or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27- (wherein R27 is as defined in the formula (I) ), or a C3-C6 alkylene group which may be substituted by a C1-C5 alkyl group. ] or ~<0~37 (wherein R22 and R23 are as de~ined in the formula (I), and 20 R32 rep~esents a hydrogen atom or a C1-C5 alkyl g~oup which may be substituted by a phenyl group ) is reduced and then o}~idized as shown in the f ollowing Scheme 4, a compound in which R6 = R7 = H among the compounds represented by the above f ormula ( I ) can be prepared .
(Scheme 4) R I OH
(V ) ~ ~\ ( O ) R Rs R~
(wherein Rl, R2, R3, R4, R5 and R8 are as already defined. ) As a reducing agent, there may be mentioned a metal hydride 35 complex compound such as lithium aluminum hydride, etc., 2~7~9~4 and as an oxidizer, there may be mentioned a metal oxidizer such as active manganese dioxide, chromic acid, etc.
2 ) ( Scheme 5 ) Rl 0 R~
R2~,~ T o~\R8 ~ I ) R3 Rs ~Xl I 1) (Xi~') (wherein Rl to R8 are as defined in the formula (I) . ) Further, for example, by condensing the compounds repre-15 sented by the above formulae (XIII) and (XIV) in a suitablesolvent such as ethanol or benzene, etc. in the presence or in the absence of a 0 . 01 equivalent amount to 10 equivalent amount of an acid, a base or a salt as shown in Scheme 5, it can be prepared. As the acid ~:o be used, there may be 20 mentioned a protonic acid such as sulfuric acid, para-toluenesulfonic acid, etc., a ~ewis acid such as boron trifluoride, etc., and the like. As the base and the salt, there may be mentioned ammonia or a salt thereof, an organic base such as piperidine, pyridine, morpholine, 1, 8-25 diazabicyclo-[5,4,0]-undeca-7-ene, etc. or a salt thereof, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc,, a metal amide such as lithium diisopropylamide, etc., a metal alcoholate such as sodium methylate, etc., an alkali metal hydride such as sodium 3 0 hyd~ide, etc ., and the like.
3) Further, for example, a compound in which R6 and R7 are hydrogen atoms or Cl-Cs alkyl groups, and R8 is represented by -COR16 (wherein R16 is as defined in the 35 formula (I) ) particularly among the compounds of the ~} ~q~ ~
.
formula (I) can be prepared according to the following Scheme 4 P~ RG ~ H 2~{R?)~ H R330H ( T ) C~ V~
~? / ( Scheme 4 ) R2~ \~\û /
R L~r7i~; acid (wherein R1, R2, R3, R4, R5, R6, R7, R17 and R18 are as 15 already defined, and R33 represents a Cl-Cs alkyl group which may be substituted by a phenyl group ) For exa~le, by reacting the acetophenone derivative represented by the above formula (XIII) with glyoxylic acid 20 without a solvent or in a suitable solvent including a hydrocarbon type solvent such as benzene, toluene, etc, an ether type solvent such as tetrahydrofuran, dioxane, etc, and the like in the presence of a catalyst including an organic acid (the organic acid can also serve as a solvent) 25 such as acetic acid, propion~c acid, etc, an inorganic acid such as sulfuric acid, phosphoric acid, etc, and the like or without a catalyst at a temperature of -50 ' C to 200 C, preferably 20 C to 150 C for 5 minutes to 48 hours, preferably 30 minutes to 5 hours, the benzoylacrylic 30 acid represented by the formula (XIV) can be prepared Further, the compound (XIV) can be also prepared by, for example, reacting the benzene or benzene derivative represented by the formula (XV) with a maleic acid anhy-dride derivative in the presence of a catalyst such as 35 aIuminum chloride, tin (II) chloride, etc (under condi-tions of the so-called Friedel-Crafts reaction) 2 ~
.
By condensing a compound represented by the f ollowing formula (XV) or (XVI):
R17 Rl 8NH ( XV ) R330H (XVI) (wherein R17 and R18 are as already defined, and R33 repre-sents a C1-Cs alkyl group which may be substituted by a phenyl group. ) 10 to the compound (XIV) in a suitable sDlvent such as tetra-hydrofuran, benzene, dimzthylformamide, etc. or without a solvent in the presence or in the absence of a condensing agent, the compound of the present invention represented by the formula (I) can be prepared. As the cDndensing agent, 15 there may be mentioned the above acids and bases, and also an inorganic ~on~ n~ing agent such as phosphorus oxychlo-ride, thionyl chloride, etc., an organic c~-nfl~n~ing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc., and the like.
Further, for example, after the compound (XIV) is reacted with thionyl chloride, phosphorus pentachloride or the like to be converted into an acid halide, or after ethyl formate, isobutyl formate or the like is made to act on the 25 above compound (XIV) in the presence Df an organic base such as triethylamine, pyridine, etc. to be converted into an active mixed acid anhydride, by reacting said halide or anhydride with the compound (XV) or (XVI) in the presence of an organic base such as triethylamine, pyridine, etc. or 30 an inorganic base such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, etc., the compound represented by the above formula (I~ can be also prepared.
Further, among the compounds represented by the above 35 formula (I), a compound in which the groups represented by R1 to R5 are -OH can be also prepared from the compound (I) in which corresponding R9 is a C1-Cs alkyl group which may be substituted by a halogen atom or a phenyl group, in a ?I~,~ql~
suitable solvent such as methylene chloride, acetonitrile, etc under dealkylation co~ditions that boron trichloride, trimethylsilane iodide, an anhydrous aluminum chloride-pyridine complex or the like is made to act.
Among the compounds represented by the above f ormula ( I ), a compound in which R8 is represented by CN can be also prepared by a dehydration reaction in which a compound in which R8 is represented by -CON~2 is reacted with thionyl 10 chloride, dicyclohexylcarbodiimide, acetic anhydride or the like in a suitable s~lvent such as dimethylformamide, dimethylsulfoxide, etc~ or without a solvent.
~he compound represented by the above ~ormula (I) of the 15 present invention or a salt thereof is useful as a tyrosine kinase inhibitor as described below, and based on its effect, there can be expected uses as a carcinostatic agent, an immunosuppressant, a platelet aggregation inhibiting agent, an arteriosclerosis treating agent, an 2 0 an t i -; n f 1 A ImnA t ory agen t, e t c .
As a preparation of the tyrosine kinase inhibitor or the carcinostatic agent according to the present invention, any preparation by oral, enteral or parenteral administration 25 can be selected. As a specific preparation, there may be mentioned a tablet, a capsule, a fine granule, a syrup, a suppository, an ointment, an injection, etc.
As a carrier o~-the tyrosine kinase inhibitor or the 30 carcinostatic agent according to the present invention, there may be used an organic or inorganic,- solid or liquid and generally inactive pharmaceutical carrier material which is suitable for oral, enteral and other parenteral administrations Specifically, there are, for example, 35 crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fat and oil, gum and 2 ~ 7 ~
.
polyalkylene glycol. The ratio of the tyrosine kinase inhibitor or the carclnostatic agenf: of the present inven-tion to the carrier in the preparation can be changed at a ratio of 0 2 % to 100 96.
Further, the tyrosine kinase inhibitor or the carcinostatic agent according to the prese~t invention may contain a tyrosine kinase inhibitor or a carcinostatic agent which is different therefrom, and other medicines. In this case, 10 the tyrosine kinase inhibitor or the carcinostatic agent according to the present invention may not be a main ingre-dient in the preparation.
The tyrosine kinase inhibitor or the carcinostatic agent 15 according to the present invention is administered generally in a dose by which a desired effect can be achieved without side effect. A specific value thereof should be r~et~rm;n~l by judgment of a doctor, but it is generally 10 mg to 10 g, preferably 20 mg to 5 g per day in 20 the case of an adult. The compound of the present inven-tion may be administered in a dose of 1 mg to 5 g, more preferably 3 mg to 1 g per day in the case of an adult as an active ingredient.
25 Best mode for practicing the invention In the following, the present inven'.ion is described in detail by referring to Examples and ~est example, but the present invention is not limited by the following examples 30 unless it exceeds its scope.
Example 1 O O
~CH3 --i 'COOH
2 ~
.
a,7 Under nitrogen atmosphere, a solution of 3, 4-dimethoxy-acetophenone (10.00 g, 56 mmol) and glyoxylic acid mono-hydrate (5.11 g, 56 mmol) dissolved in 11 ml of acetic acid was refluxed unaer heating for 20 hours. The reaction 5 mixture was cooled, and the precipitated solid was collected by filtration, washed with acetic acid and then dried by heating to give 7.75 g (yield: 59 %) of the above carboxylic acid.
m.p. 175 to 177 C
1H NMR (DMSO, 250 MHz) ~ ppm: 3.86 (s, 3H), 3.89 (s, 3H), 6.68 (d, lH, J=15 4Hz), 7.11 (d, lH, J=8.5Hz), 7.51 (d, lH), 7.77 (dd, lH, J1=2.0Hz, J2=7.8Hz), 7.94 (d, lH, .J=15 . 5Hz ) .
Example 2 O O
L~ DX~ 0 HA
I,I~O~o To a suspension of the above carboxylic acid (1.5 g, 6.36 mmol) obtained in Example 1 in 10 ml of carbon disul Eide was added phosphorus pentachloride ( 1. 6 g, 7 . 63 mmol ), and 30 the mixture was refluxed under heating for 15 minutes. A
solution of the residue obtained by cooling and then concentrating the reaction mixture, dissolved in 5 ml of dichlorom~thi~n~ Mas added to 5 ml of concentrated aqueous ammonia under ice cooling. The precipitated solid was 35 collected by filtration, washed with 1 N NaOH and water in ~ ~J7i~9~4 this order and then dried to give 900 mg (yield: 60 %) of an a~[ide compound.
m.p. 188 to 190 C
lH NMR (250 ~XZ, D~SO) ~ ppm: 3.85 (s, 3H), 3.88 (s, 3H), 6.95 (d, lH, .J=15.3HZ), 7.12 (d, lH, J=9.3Xz), 7.51 (s, 1~l), 7.54 (s, lH), 7.76 (d, lH, J=8.7Hz), 7.82 (d, lH, J=15.5Hz), 7.85 (s, lH):
10 A dimethylformamide solution (5 ml) of the amide compound (500 mg, 2.13 mmol) was stirred on an ice bath, and thionyl chloride (0.31 ml, 4.2 m.~ol) was added thereto. After the mixture was stirred at room temperature for 20 minutes, water was added to the reaction mixture, and the product 15 was extracted with ethyl acetate The resi~ue obtained by washing the extract with brine was dried (anhydrous magne-sium sulfate), conce~trated and recrystallized ~rom hexane-ethyl acetate to give a desired nitrile compound (220 mg, 47 %).
m.p. 132 to 135 'C, pale orange- crystal H NMR (250 ~![Hz, CDC13) ~ ppm: 3.96 and 3.99 (2s, 6H), 6.57 (d, J=16.0HZ, lH), 6.95 (d, 3=8.3HZ, lH), 7.50 to 7.70 (m, 2H), 7.84 (d, J=16.0Hz, lH) .
25 IR (1~}3r) cm~l: 3000, 3036, 2222, 1664, 1609, 1582, 1520, 1354, 1277, 1128, 772.
Exampl e 3 ~leO C~)7~ 71~e To a dichloroethane solution ( 6 ml ) of the carboxylic acid (1.00 g, 4.24 mmol) obtained in Example 1 were added methanol (0.52 ml, 12.72 mmol) and concentrated sul:Euric ~ 9 1 ~
acid (0.014 ml), and the mixture was refluxed under h-eating ~or 2 hours. Water was added to the reaction mixture, the product was extracted with ethyl acetate, and the extract was washed with a saturated jodium hydroyen carbonate 5 a~aueous solution and then dried (anhydrous magnesium sulfate) ~rnder reduced pressure, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (developing solution: n-hexane/ethyl acetate = 5~1) to give a desired methyl ester compound (610 mg, 57 9~
m.p. 90 to 93 C, pale yellow crystal H N~qR ~250 MHz, CDCl3) ~ ppm: 3.85, 3.96 and 3 98 (3s, 9H), 6.89 (d, J=15.5Hz, lH), 6.93 (d, J=8.4Hz, lH), 7.58 (d, J=2.0Hz, lH), 7 66 (dd, J=2.0, 8.4H2, lH), 7.95 (d, J=15 5H2, lH) .
IR (~Br~ cm~l: 2944, 2851, 1721, 1665, 1622, 1580, 1449, 1420, 1306, 11S5, 1019, 766.
20 Example 4 D D
) 0~ O~h' ~20 1~20 By using 4-methoxyacet-)rh~none as a starting substance, the above methyl 2-(4-methoxybenzoyl)acrylate was obtained by the same method as in Example 1 and Example 3 (overall yield: 20 9~;).
m.p 75 to 76 C, pale yellow crystal IR (KBr) cm~l: 2948, 2847, 1717, 1669, 1626, 1595, 1512, 1447, 1339, 1308, 1263, 117I, 986, 837, 768, 596.
35 Example 5 ~ ~7~8~4 O O
OHC-C02H ~--CD2M -- *
o ~CO~lHPh 10 By using propiophenone as a starting substance, a reaction was carrled out by the same method as in Example 1 to obtain a corresponding carboxylic acid (yield: 29 ~6). A
tetrahydrofuran solution (20 ml) of this carboxylic acid (1.04 g, 5.54 mmol) was stirred under nitrogen atmosphere, and triethylamine (0.97 ml, 7.0 mmol) and aniline (0.64 ml, 7 . 0 mmol) were added thereto. The reaction mixture was cooled on an ice bath, phosphorus oxychloride (0.78 ml, 8.4 mmol) was added thereto, and the mi2~ture was stirred at room temperature overnight. Water was slowly added to the 20 reaction mixture, the mixture was concentrated under reduced pressure, -water was further added to the concen-trate, and the product was extracted with ethyl acetate (70 ml). The extract was washed success~vely with a saturated sodium hydrogen carbonate aqueous solution, ~[iluted hydro-25 chloric acid and water and dried over anhydrous sodiumsulfate. Under reduced pressure, the solvent was removed by evaporation, and the obtained solid was recrystallized from ethanol-water to give the desired above-mentioned amide compound (170 mg, 11 %).
H N~ (250 MHz, CDCl3) ~ ppm: 2.45 (d, J=1.3Hz, 3H), 6.26 (q, J=1.3Hz, lH), 7.13 (t, J=7.4Hz, lH), 7.33 (t, J=7.4Hz, 2H), 7.40 to 7.65 (m, 6H), 7.75 to 7.85 (m, 2H).
m.p. 128 to 129 C, colorless needle crystal Example 6 2~8~
O O
[~~1~ ~) E~3N ~
Under nitrQgen atmosphere, methanol (6 ml) was cooled to -20 'C, and 0.34 ml (4.7 mmol) of thionyl chloride was added thereto. Aiter the temperature o~ the solution was raised to -lO Cr the above carboxylic acid (560 mg, 3.14 10 mmol) synthesized by the method o~ R E Lutz et al. [J. Am.
Chem. Soc., 75, 5039 (1953) ] was added thereto. The mixture was stirred at room temperature lor 3 days and then concentrated under reduced pressure to give an exo-methyl-ene methyl ester compound (450 mg, 70 %) . To an ether 15 solution (6 ml) of this exo-methylene=methyl ester compound (360 mg, 1.76 mmol) was added triethylamine (2 ml), and the mixture was stirred at room temperature ~or 5 days. After the mi~ture was con~-Pn~r~t~d under reduced pressure, the residue was puri~ied by applying it to silica gel column 20 chromatography (developing solution: n-hexane/ethyl acetate = 10/1) to give the desired above methyl ester compound (260 mg, 72 %) as an oily substance.
lH NMR (250 MHz, CDCl3) ~ ppm: 2.20 (d, J=1 3Hz, 3H), 3 86 25 (s, 3H), 7.'L5 to 7.65 (m, 3H), 7.73 (q, J=1.3Hz, lH), 7 95 to 8 . 02 (m, 2H) .
Example 7 Z~ ONHPn By using ~he above carboxylic acid synthesized by the 35 method o~ R.E Lutz et al [J Am Chem Soc, 75, 5039 (1953) ~, amidation was carried out by the same method as in Example 5 to give a desired anilide compound (yield: 58 %).
IH NMR (250 MHz, CDCl3) ~ ppm: 2 34 (d, J=1 4Hz, 3H), 7.17 (t, J=7.4Hz, lH), 7 31 to 7 42 (m, 2H), 7.43 to 7.65 (m, 6H), 7.74 (brs, lH), 7 95 to 8.03 (m, 2H) .
m.p 127 to 128 C, pale yellow columnar crystal Example 8 D
i * ~ [~(CH3~=c(cH~)G~N3~h 20 By using the abo~re lactone compound synthesized according to the method of R.E. Lutz et al. [J. Am. Chem. Soc., ~, 5039 (1953) ], amidation was carrled out by the same method as in Example 5 to give a desired a~ilide compound (yield:
73 %)-H NMR (250 MHz, CDCl3) ~ ppm: 1 85 and 1.89 (2d, J=0 8Hz, 6H), 6 . 73 (m, 2H), 6 . 85 ( t , J=7 . 4Hz , 1H), 7 . 11 ( t , J=7 . 9Hz , 2H), 7 . 37 (m, 3H), 7 . 52 (m, 2H) .
m.p. 218 to 221 C, white crystal Example 9 H
B r ` ~ J~
NH . -- - ~ ~N
\1/ \1/
2 1 ~ ,g~
Under nitrogen atmosphere, an acetone suspension (15 ml) oE
diisopropylamine (4.05 g, 40.0 mmol) and potassium carbonate (6.91 g, 50.0 mmol) was cooled to 5 'C, and while stirring the suspension, propargyl bromide (3.01 ml, 40.0 5 mmol) was added thereto. After the temperature of the reaction mixture was raised to room temperature over 2 hours, the mixture was further stirred at room temperature for 3 honrs. To the residue obtained by removing precipi-tates by filtration and concentrating the filtrate was 10 added water, and the product was extracted with dichloro-methane (50 ml). After the extract was dried over sodium sulfate, the solvent was removed by evaporation under reduced pressure to give oily propargylamine (2.78 g, yield: 50 %).
H NMR (250 MHZ, CDCl3) ~ ppm: 1.10 (d, J=6.5HZ, ~2H), 2,13 (t, J=2.5HZ, lH), 3.20 (hep, J=6.5HZ, 2H), 3.42 (d, ~=2 . 5HZ, 2H) .
Example 10 H ~ 0 \1/ ~eO~
~
Under nitrogen atmosphere, a tetrahydrofuran solution (40 ml) of the propargylamine (1.39 g, 10.0 mmol) obtained in Example 1 was cooled to -70 C, and while stirring the solution, a 1. 56 M n-butyl lithium solution was added 30 dropwise thereto. After the temperature of the reaction solution was slowly raised to O C, the solution was cooled to -70 C/ and a tetrahydrofuran solution (10 ml) of 3,4-dimethoxybenzaldehyde (1.66 g, 10.0 mmol) was added drop-wise thereto. After the temperature of the reaction 35 mi2~ture was raised to O C over 2 hours, water was added thereto to terminate the reaction. Unaer reduced pressure, 2 ~ 4 .
the solvent was removed by evaporation, and then the product was OEtracted with dichloromethane ~40 ml x 2).
After the extract was dried over: anhydrous sodium sulfate, the solvent was removed by evaporation under reduced 5 ~)L~ U.C'c:. The residue was purified by silica gel column chromatogre~phy (CHCl3: MeOH = 20: 1) to give the above-mentioned amino-alcohol (3.00 g, yield: 98 ~6) as an oily subs tance .
10 lH ~R (250 3~Hz, CDC13) ~ ppm: 1.10 (d, J=6.5Hz, 12H), 2.40 (brs, lH), 3.20 (hep, J=6.5Hz, 2H), 3.51 (d, J=1.7Hz, 2H), 3.89 and 3.90 (2s, 6H), 5.42 (brs, 1~), 6.85 (d, J=8.1Hz, lH), 7 . 07 (m, 2H) .
15 Example 11 Dll D~l A tetrahydrofuran solution (10 ml) of the propargyl alcohol (1.02 g, 3.10 mmol) obtained in Example 10 was added drop-wise to an ether solution (30 ml) of 330 mg (8.7 mmol) of lithium aluminum hydride cooled to -30 C. After the 25 mixture was stirred at room temperature for 2 days, water (1 ml) was slowly added to the react-on mi~ture while ice cooling . Af ter the mixed solution was stirred at room temperature for a while, insolubles was filtered with celite, and the filtrate was concentrated. The residue was 30 purified by silica gel column chromatography (developing solution: chloroform/methanol = 30/1 to 5/1) to give an allyl alcohol compound (719 mg, 76 %).
lH NMR (250 lMHZ, CDC13) i~ ppm: 1.05 (d, J-6.6Hz, 12H), 2.10 35 (brs, lH), 3 11 (hep, ~=6.6Hz, 2H), 3.13 (d, J=3 8Hz, 2H), 2 ~
.
3 87 and 3 38 (2s, 6X), 5 .17 (m, lH), 5 83 (m, lH), 6 . 80 to 6 . 95 (m, 3H) .
Example 12 OH
MeO ~ ~ ) MnO
A'eOf~J ~~ ~) HO
/~
~eO~O
MeO
15 A dichloromethane solution (50 ml) of the allyl alcohol compound (710 mg, 2 . 32 mmol) synthesized in Example 11 was vigorously stirred at room temperature, and active man-ganese dioxide (7.1 ~) was gradually added thereto. After stirring was continued for 1.5 hours, the reaction mixture 20 was filtered with celite, and the filtrate was concentrated to give a ketone compound ( 45 0 mg, 64 % ) .
H NMR (250 MXz, CDCL3) ~ ppm: 1 03 (d, J=6.5Hz, 12H), 3.06 (hep, ,J=6 5Hz, ~H), 3.34 (d, ,J=4 4Xz, 2H), 3.95 (s, 6H), 6.91 (d, J=8.2Hz, lH), 7.06 (dt, J=15.1, 4 4Xz, lH), 7 19 (d, J=15.1Hz, lH), 7.55 to 7.65 (m, 2H) .
An ether solution ( 8 ml ) of the obtained ketone compound (116 mg, 0 38 mmol) was cooled with ice, a 7 % by weight of 30 hydrogen chloride acetic acid solution (0.7 ml) was added thereto, and the mixture was stirred at the same tempera-ture for 15 minutes Precipitated amine hydrochloride (109 mg, 84 96) was isolated by filtration.
lH MMR (250 MHz, D~So-d~ ~ ppm: 1 33 and 1.36 (2d, J=ll OHz, 12H), 3 69 (m, 2H), 3 85 and 3 87 (2s, 6H), 4.10 217~
(m, 2H), 7.05 (dd, J=6.8, 15.1xz, lH), 7.13 (d, J=8 5Hz, lH), 7.53 (d, J=1.7Hz, lH), 7.65 to 7.80 (m, 2H) .
Example 13 H - - ~) MeO ~ " N~
10 By using 3-piperidinepropyne (Japanese Provisional Patent PublicatiDn Mo. 9~755/1979) as a starting substance, the a'Dove amine compound was obtained by the same method as in Examples 10 to 12 (overall yield: 20 %).
lH MMR (250 MHz, CDCl3) ~ ppm: 1.40 to 1.55 ~m, 2X), 1.62 (m, 4H), 2.45 (m~ 4H), 3.22 (m, 2H), 3.95 and 3.96 (2s, 6H), 6.90 (d, ~=8.3Hz, lH), 7.00 to 7.10 (m, 2H), 7.50 to 7.70 (m, 2H) .
20 To an acetone solution (5 ml) of the obtained amine com-pound (360 mg, 1.30 mmol) was added an acetone solution (10 ml) of fumaric acid (75 mg, 0 . 65 mmol), and the mixture was stirred at room temperature for 30 minutes. The precipi-tated crystal was collected by filtration and washed with 25 acetone :t-o give fumarate of the above amine compound (180 mg, 35 %)-H MMR (250 MHz, DMSO-d) ~ ppm: 1.35 to 1.50 (m, 2H), 1.50 to 1.63 (m, 4H), 2.45 to 2.65 (m, 4H), 3.34 (d, J=6.3Hz, 2x), 3.81 and 3.84 (2s, 6H), 6.57 (s, 2H), 6.83 (dt, J=15 3, 6.3Hz, lH), 7.07 (d, J=~.5xz, lH), 7.30 (d, J=15.3Hz, lH), 7.47 (d, J=1.8Hz, lH), 7.67 (dd, J=1.8, 8 . 5E~z, lH ) .
m.p. 143 to 144 ~C~ colorless powder crystal 21~9~4 IR (Ksr) cm~1: 3449, 2946, 2773, 2596, 1671, 1626, 1581, 1518, 1424, 1393, 1354, 1277, 1242, 1204, 1157, 1022, 766, 632 _ 5 E~ample 14 OH O
~ NeOX~ --N --O SPh lleO~ ~ N
I(eO
A dichloromethane solution (50 ml) of the amino-alcohol (1,20 g, 3.93 mmol) obtained in Example 10 was vigorously stirred at room temperature, and active manganese dioxide (12.0 g) was added to this solution. After 1 hour, 20 insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to give the above ynone compound (715 mg, yield: 60 %) which was a desired com-pound, as a brown oily substance.
o S ~eO~
~(eO ~
lH NM~ (250 MHz, CDCl3) ~ ppm: 1.16 (d, J=6.5Hz, 6H), 3.27 (sep, J=6.5Hz, lH), 3.73 (s, 2H), 3.94 and 3.97 (2s, 6H), 6.94 (d, J=8.5, lH), 7.62 (d, J=1.8Hz, lH), 7.84 (dd, J=1. 8, 8 . 5Hz, lH) .
To an ether solution (5 ml) of the obtained ynone compound (320 mg, 1.05 mmol) were added thiophenol (110 111, 1.07 mmol) and a trace amount of piperidine, and the mixture was ' 58 stirred at room temperature for 4 hours. Under reduced pressure, the mixture was concentrated, and the residue was purified by silica gel column chromatography (developing solution: n-hexane/ethyl acetate = 2/1) to give a thio-5 phenol adduct (219 mg, 50 %) which was a desired substance.
O SPh J~l~eO~ ~ N
~leO
H NMR (250 MHz, CDCl3) ~i ppm: 0.91 (d, J=6.6Hz, 12H), 2.97 (hep, J=6.6Hz, 2H), 3.02 (d, J=1.4Hz, 2H), 3.96 (s, 6H), 6.93 (d, J=3.3Hz, lH), 7.35 to 7.g5 (m, 3H), 7.55 to 7.70 (m, 4H), 7.81 (t, J=1.4Hz, lH) .
m.p. 120 to 122 C, pale yellow crystal Example 15 ~eO~ N
~(eO `f l~eO~CH=C(~iO2Ph)CH~Y
To an ethanol solution (4 ml) of the ynone compound (120 mg, 0.38 mmol) obtained in Example 14 and sodium benzene-sulfinate (76 mg, 0.38 mmol) was added acetic acid (25 ~
0.42 mmol) at room temperature, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added water (10 ml) and saturated sodium hydrogen carbonate (10 ml), and the product was extracted with chloroform (20 ml). The extract was dried (anhydrous 2~ 789~
~9 (anhydrous sodium sulfate) and concentrated, and the residue was purified by silica gel chromatography to give the desired above-m~n~;on~1 vinyl sulfone compound (93 mg, 55 96).
50 ~0 ~h J`
~0 10lH NMR (250 MHz, Cr)Cl3) ~ ppm: 0.90 (d, J=6 5Hz, 12H), 2.95 (hep, J=6.5H7, 2x), 3.32 (s, 2H), 3.95 and 3.97 (2s, 6H), 6.94 (d, J=8.4Hz, lH), 7.42 (brs, lH), 7.45 to 7.70 (m, 5H~, 7 . 96 to 8 . 05 (m, 2H) .
m.p. 167 to 169 ~, orange powder crystal IR (K33r) cm~l: 2972, 1651, 1586, 1514, 1466, 1421, 1318, 1271, 1213, 1173, 1146, 1088, 1017, 762, 729, 615, 602, 557 .
Example 1 6 O O
~1~0~ \~ o~N
~r~der nitrogen atmosphere, to a tetrahydrofuran solution (15 ml) of cuprous cyanide (179 mg, 2 . 0 mmol) was added dropwise a 1.5 M methyl lithium ether solution (2 7 ml, 4.0 mmol) at -50 C, and the mixture was stirred for 2 minutes.
The solution was cooled to -70 C, and a tetrakydrofuran solution (6 ml) of the ynone compound (289 mg, O.9S mmol) obtained in Example 14 was added dropwise thereto . Af ter tke temperature of the reaction mixture was slowly raised to roolll temperat~ure, the mixture was cooled to 0 ' C, and a saturated ammonium chloride aqueous solution and aqueous ammonia were added thereto. After the product was extracted with ether (20 ml x 2) and dried (anhydrous ~ ~ 7~
sodium sulfate), the solvent was removed by evaporation ul~der reduced pressure. ~he residue was purified by silica gel column chromatography (developing solution: n-hexane/
echyl acetate = 2/1) t~ give the above-mentioned desired 5 compound (160 mg, 53 %) as an oily substance.
O .~.c ~I ~ D ,~
11~0/~ --1' H NMR (250 MXz, CDCl3) ,S ppm: 1.03 (d, J=6.6Hz, 12H), 2.11 (s, 3H), 3.0~ (hep, J=6.6Xz, 2X), 3.15 (s, 2H), 3.95 (s, 6H), 6.91 (d, ~=8.1Hz, lH), 7.23 (m, lH), 7.57 (s, lH), 7.59 (dd, J=1.9, 8.1Hz, lH) ~xample 17 - -o ~ X~Et ~ ~[eO < ~IEt ~
By using the above-m.onti r. nr~rl 3- (diethylamino) -3-methyl-butyne prepared according to the method of A. P . Poisselle et al. [J. Org Chem., 26, 725 (1961) ~ and the method of R.S Xznze1 et al. [J Am Chem. Soc., 82, 4908 (1960) ] as a starting substance, the above-mentioned amine compound was obtained by the same me~hod as in Examples 10 to 12 (overall yield: 59 96) .
a U~O~>< NE~7 Inr~O
lH NMR (250 MXz, CDCl3) ,S ppm: 1 06 (t, J=7.1Hz, 6H), 1 28 35 (s, 6H), 2.58 (q, J=7.1Hz, 4H), 3.95 and 3.96 (2s, 6H), 21~8914 .
6.87 (d, J=15.7Hz, lH), 6.91 (d, J=8.0Hz, lH), 7.09 (d, J=15.7Hz, lH), 7.55 to 7.62 (m, 2H) P~n ether solution of the above-mentioned amine compound obtained (100 mg, 0 33 mmol) was cool~d with ice, a 7 96 hydrochloric acid ethyl acetate solution (2 ml) was added thereto, and the mixture was stirred at the same tempera-ture for 15 Tninutes The precipitated solid was collected by filtration and dried to give hydrochloride of the above-mentioned amine compound (75 mg, 67 %) .
o ~~X N~t~
1~0 ~{C
H MMR (2~0 r~Hz, CDCl3) ~ ppm: 1.57 (t, J=7.4Hz, 6H), 1.83 (s, 6H), 3.05 and 3.46 (2m, 4H), 3.97 and 3.99 (25, 6H), 6.96 ~d, J=8 5Hz, lH), 7.11 (d, J=15.7Hz, lH), 7.63 (d, J=15.7Hz, lX), 7,63 (d, J=1 9Hz, lH), 7.77 ~dd, J=l.9, 20 8.5Hz, lH), 11 82 (brs, lH) .
m.p. 214 to 215 '~, white powder crystal Example 18 x~ D <~
By using 3-piperidine-3-methyl-butyne as a starting 30 substance, the above-mentioned amine compound (overall yield: 24. %) and hydrochloride (yield: 73 %) were obtained by the same method as in Example 17 The respective da~a are shown belo~.
.
~leO I ~, / ~, ~3 ~eO
H NMR (250 MHz, CDCl3) ~ ppm: 1.25 (s, 6H), 1.40 to 1.50 (rn, 2H), 1.50 to 1 65 (m, 4E~), 2.53 (m, 4H), 3.95 and 3.96 (2s, 6H), 6.88 ~d, J--15.4Hz, lH), 6.91 (d, 3=8.0Hz, lH), 7.C7 (d, J=15.7Hz, lH), 7.50 to 7.62 (m, 2H) .
10 Pale yellow oily substance ~leO~
~eO
~ C s~
H MM~ (250 MHz, CDCl3) ~ ppm: 1.79 (s, 6H), 1.80 to 2.00 (m, 4H), 2.45 to 2.80 (m, 4H), 3.60 to 3 75 (m, 2H), 3.97 a~d 3.99 (2s, 6~), 6.96 (d, J=8 4Hz, lH), 7.07 (d, J=15.7Hz, lH), 7.54 (d, J=15.7Hz, lH), 7.62 (d, J=1.9Hz, lH), 7.75 (dd, J=l.9, 8 4Hz, lH), 12.10 (brs, lH) .
m.p. 255 'C (dec~, colorless powder crystal E}~ample 1 9 ~ X~IE L 2 ~ U ~O~ E ~, 3 0 ~I~D~J~C~=C (S02 ~h) l~e 0 7\~E t 2 By using 3-dimethylamino-3-methylblltyne as a starting 35 substance, the above-mentioned ynone compound was synthesized (see E2~ample 10 and Example 14, overall yield:
2 ~ ~89 ~ ~
64 ~), and further a vinyl sulfone compound (yield: 46 %) was obtained by the same method as in Example 15.
O
ILoO~
l~J ~ NEt l~I ~R (250 MHz, CDCl3) ~ ppm: 1.13 ~t, J=7.1Hz, 6H), 1.54 (s, 6H), 2.78 (q, J=7.1Hz, 4H), 3.95 and 3.97 (2s, 6H), 6.94 (d, J=8.gHz, lH), 7.63 (d, J=1.9Hz, lH), 7.84 (dd, J=1 9, 8 . 4Hz, lH) .
~ ~(e~ ~S0 Pn lH NMR (250 MHz, CDCl3) ~ ppm: 0.96 (t, ~J=7.1Hz, 6H), 1.35 (s, 6H), 2.91 (q, J=7.1Hz, gH), 3.96 ~s, 6H), 6.96 (d, ~=8.2Hz, lH), 7.45 to 7.70 (m, 5H), 7 84 (s, lH), 8.05 to 8 . 10 (m, 2H) .
m.p. 133 to l3a C, pale yellow powder crystal IR ~K}3r) cm~l: 2975, 2938, 1655, 1597, 1586, 1512, 1449, 1418, 1306, 1269, 1209~ 1169, llg6, 1086, 1020, 756, 741, 69g, 6g2, 561.
Reference example 1 ~_5Q C ~ ~ ~SC~ila 20 ml of an aqueous solu~ion of sodium sulfite (5.0 g, 39.9 mmol) and sodium hydrogen carbonate (3 . 5 ~, 42 . 0 mmol~ was 35 heated to 80 C by an oil bath, p-toluenesulfonyl chloride (4 0 g, 21. 0 mmol) was added thereto, and the mixture was 7~7~9~
heated at 80 C ~or 4 hours. After cooling, crystal was collected by filtration and dried under reduced pressure.
~he crystal was used for the next reaction without carrying out further purilication. (yielded amount: 2,7 g, yield:
5 7~ ~) ~ SO 2Na 10 lH NMR (250 MHz, DMSO-d6) ~ ppm: 2.29 (s, 3H), 7.12 (d, J=7.9Hz, 2H), 7.38 (d, J=7.9Hz, 2H) .
Colorless powder In the same manner as in Reference ex~nple 1, the co~pounds 15 of Reference e2~Lples 2 to 4 were prepared by usin~ commer-cially available sulfonic acid chlorides. In the follow-ing, the structures of the used acid chlorides and the desired compounds and the physical properties and yields of the desired compounds are shown.
Refer- Sulfonic Sodium 1H-NMR (250 Yield e~nple acid sulfinate MHz, DMSO-d6) 7 . 71 (d, J=
~2~S02CI N02~so2N~ 8 12 (d, J- 69 8.6Hz, 2H) - 6.92 to 6.97 3 ~1 ~1 (m, 2H), 7 40 75 ~S/~SO2Cl ~S~SO2Na (d, J=4 5Hz, 4 MeS02Cl MeS02Na 1.95 (s, 3H) 20 Example 20 ~o ,11~
~leOX~ ~NE~ 2 o .I~IeO~J!~cH-c(so2c6H4-p~e)c~e2NE~2 lleO
Acetic acid (75 ml, 1.32 mmol) was added to an ethanol solution (10 ml) of the ynone compoun~ (400 mg, 1.32 mmol) obtained in Example 19 and sodium p-toluenesulfinate (350 mg, 1.98 mmol) obtained in Reference example 1 at room lQ temperature, and the mixture was stirred at room tempera-ture for 24 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, then 20 ml of water was addea to the concentrate, and the mixture was extracted twice with each 20 ml of chloroform. The organic 15 layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated saline solution, dried over anhydrous sodium sulfate and then filtered. The residue obtained after concentration under reduced pressure was applied to silica gel column chromatography (n-hexane-20 ethyl acetate = 3: 1) to give a vinyl sulfone compound(280 mg, 46 %) from a desired fraction.
o lleoX~CH=C(S02C6H4-P~le)CYe2~et2 NMR (250 MHz, CDC13) ~ ppm: 0.98 (t, J=7.1Hz, 6H), 1.34 (s, 6H), 2.42 (f, J=7.0Hz, 4H), 2.43 (s, 3H), 3.96 (s, 6H), 6.95 (d, J=8.3Hz, lH), 7.33 (d, J=8.1Hz, 2H), 7.50 (dd, J=8.3, l.9Hz, lH), 7.58 (d, J=1.8Hz, lH), 7.82 (s, lH), 7.94 (d, J=8.3Hz, 2H) .
m.p. 75 to 77 C, colorless powder IR (Ksr) cm~1: 2971, 1659, 1595, 1514, 1464, 1418, 1306, 1269, 1144, 1024, 818, 758, 723.
21~14 By using the sodium sulfinates prepared in Reference exam-ples 2 to 4 and the ynone compound obtained in Example 19, the compounds of Examples 21 to 23 were prepared in the same manner as ~n the ~Lethod of Example 20. In the follow-5 ing, the structures of the sodium sulfinates used and thedesired compounds and the physical properties and yields of the desired compounds are shown.
2 ~ 7~9 ~ ~
~ . . .~
~ `-- _ . .
æ ~ ~Uq~ 0~ g _. . . _ ~ -- i -- ~. ,n _ _ --. 2 = ~ _ 2 ~
2 q ~ ~ 0 ~ = ~ = ~ = ~ ~ ~ ~ 2 cn . _ ~ O~ ~ O = G = = o d ,~, _ -o~ r~ !
r - ~ z ~ w '~ r~
c) o o ro~J o o ~ o q 1 4 - , .
D ~ , -- ~ t-`'~
t~ ~ ~ ~ ~ C
C ~
_ _ _ ~ t~ ~
oJ
CO~
L
E ~ .:
o ~ ~
~ ~ZO
2~ 7~91~
By using amino-alcohols prepared from the respective aldehydes and propargylamines in the same manner as in the method of Example 10, ynone compounds were prepared in the same manner as in E7cample la.. By using the o~tained ynone 5 compounds and using sodium benzenesulfinate, the compounds of E~camples 2~ to 28 were prepared in the same manner as in the method of Example 15 In the follo~ing, the structures of the used ynone compounds and the desired compounds and the physical properties and yields of the desired compounds 10 are shown.
2 1 789 l ~
. =, ~ ~ ~r ~ L
S cr: ~ ~ _ ~- ~
~ _ _ _ _ . _ ~ _ _ ~ æ ~ 0 ~ =~ O ~ S--Q
Q
~<
(~ O ~
pUrlOL~IO~I auor;~; puno~ o::~ pallsaa ~ ~ o C~
--q l ~
.
~ , . ~ . ~ i , ,~
o O ~V _ _ _ _ Lr~
cr , q , O c ~ ,_ ~ ~ O O ; ,_ -- r ~l Cq Cq . -- ~ r~ ~ Cq ~ Lq r ~ :~
_ C~ ~ ~ ~ O ~ rr' _~ ~ ~ ~ =
rrr q O = _ .5 _ _ 3 `_ q ~q $
r~ --~ =, ~ ~ ~ . Cq = =-5r rr~ 5 _ 3 ~ -"
_~, æ ~ q ,~
c~ - ~3 q ~r ~r r q ' q ,-- O
' 'q r-- t~
r,~ ~ ~ . W
Q
L Q
"~ o~
o~
o~
~, , . . . .
punoduloa auou~ p-.modlllo~ pallsaa , .
~ 72 .-- . . . ;
a) ~ ~
~ . , . . -~
o ~ ~
33 ~ ~ e U L'~ ~ ~ U ~~) 8C~ q ;~ cL~ ~ 0 ~ G
~ _ C~ N
C ~
~ _ ~ ~ , _ _ _ C~~ O ' ' ~ = ~ =
^ -- -- C 1~
__ _ _ ~ C`~ _ ~ O~ _ -- ~ ~: O 1:-- ~ ~ ~ L" C~ O
Q
..
,~ .
o ~/ ~r \~
o o punodllo~ auor~T,C punodu}oa p~31L5 o -2178~14 o o ~ ~ -- ~ q ~ ~ ~ o o C~ ~ ~ ; O ~ ~ ~ ~ q ~
q q C~ _ ~'~ ~ ~ ~q ~
~ C~
-- o _ o _ C'~ o ~ q c~ C~
C~ ~ C~ O ~ = ~ --~ ' D O - - ' cq -- ~ ~ ~ ~q c--~ -qq o ~
~ ~ ~ $
_ _ t~: r~ -~D C~:-- O ~ 2~i 1 3 _ _ Q
Q
V
,~ o , o~ .
o~
o~
p~oaulo~ ~uou~ puno~o~ p~lS~a ~' ~Z
, . ~ =
3 ", ~ ;~ o Il. O ~ P.~ O
~~_ O ~
- ~ - ~ ~ ~ ~ ~ - ~ o 3 ~ 1-- 0 ~ ~ ~
Q
Q
X G
punoduloa ~3uou~ punoduloa pal~s~3~
o ~
D~ Z =, . , I
2 ~ 7~9 ~ 4 .
Example 2 9 OH
H ~(~o ~
S ~ NfI ~ ,~ XN~
~O ,L~
~0~ X
Molecular sieve 4A (10 g) was added to a tetrahydrofuran solution (50 ml) of 3-amino-3-methyl-1-outyne (S O g, go %
in H20, 54 mmol), and the mixture was stirred under nitro-gen atmosphere for 30 minutes. Under nitrogen atmosphere, the molecular sieve was removed by filtration, and the filtrate was cooled by a dry ice-ethanol bath. To this filtrate was added dropwise a 1.63 M n-butyl lithium hexane solution (33.0 ml, 54.0 mmol) over 2 hours. After the temperature of the reaction mixture was slowly raised to O
C, the mixture was cooled again by a dry ice-ethanol bath, and veratraldehyde (8.97 g, 54 0 mmol) was added thereto.
Af ter the temperature of the reaction mixture was raised to room temperature, the mi~ture was cooled to O C, and water was added thereto to terminate the reaction Af ter the solvent was removed by evaporation under reduced pressure, water was added to the residue, and the product was extracted with dichloromethane (70 ml x 2) . The extract was dried (anhydrous sodium sulfate) and concentrated, and the obtained oily substance was purified by silica gel column chromatography (developing solution: chloroform/
methanol = 50/3) to give amino-alcohol (7 65 g, 57 %) which was an adduct.
3s Amino-~l cohcl coTnnol~ntl 2~78914 lH NMR (CDCl3, 2~0 MHz) ~ ppm: 1.44 (s, 6H, 1.98 (brs, 3H), 3.89 and 3.90 (2s, 6H), 5.41 (s, lH), 6.86 (d, J=8.7Hz, lH), 7 . 03 to 7 .10 (m, 2H) .
m.p. 85 to 87 C, pale yellow crystal At room temperature, to a dichloromethane solution (50 ml) of the above-mentioned amino-alcohol (1.65 g, 6.59 mmol) was added active manganese dioxide (10 2 g) 10 times each in an amount divided into 10. After 2 minutes, the 10 reaction mixture was filtered with celite, and the residue was washed with dichloromethane (20 ml). The filtrate was concentrated to give an ynone compound (1.39 g, 85 %).
IIBO~ XNH2 lH NMR (250 MHz, CDCl3) ~ ppm: 1.54 (s, 6H), 1.78 (brs, 2H), 3.95 (s, 3H), 3.97 (s, 3H), 6.94 (d, J=8.4Hz, lH), 7.6~ (d, J=2.0Hz, lH), 7.81 (dd, J=8.3, l.9Hz, lH) .
Pale yellow oily state O O
25 UeO~\ X~H2 ~`~; X
llea~ CH=C(S02Ph) XNH2' HC ~
By using the above aminoynone compound (200 mg, 0.82 mmol) and sodium benzenesulfinate (160 mg, 0.82 mmol), a vinyl sulfone compound (21û mg, 66 96) was obtained in the same manner as in Example 20. This compound was dissolved in a .
2~ 7rd914 .
mixed solvent of diethyl ether (60 ml~ and ethyl acetate (20 ml), and the solution was stirred under nitrogen atmos-phere on an ice bath A 4 N hydrochloric acid-ethyl acetate solution (0.3 ml) was added dropwise thereto, and 5 the mixture: was stirred at the same temperature for 10 minutes. The produced precipitates were collected by filtration, dried and suspended in ethyl acetate-diethyl ether (1/5) . After stirring for :10 minutes, the precipi-tates were collected by filtration to give hydrochloride of 10 a desired vinyl sulfone compound (200 mg, 91 %) .
o ~{eO~ ~H=~(SO2~n~x}~H2 3~C
lH NMR (250 MHz, CDC13) ~ ppm: 1.90 (s, 6H), 3.86 (s, 3H), 3.94 (s, 3H), 6.95 (d, J=8.5H~, lH~, 7.41 to 7.60 (m, 5H), 8.02 (dd, J=8.3, l.9Hz, lH), 8.12 (dd, J=7.9, l.OHz, 2H), 9.19 (brs, 2H).
IR (KBr) cm 1 3407, 3227, 2841, 2037, 1658, I588, 1514, 1443, 1422, 1310, 1269, 117:3, 11a.6, 1080, 1019, 752, 632.
m.p. 149 to 151 C, yellow columnar c~ystal Example 30 O O
~leO ~J~ 0 ,~
MeO~ YEt 2 ~ ~ `C~l=C(C~Y)Cb!e2,YEt2 30 The ynone compound (200 mg, O . 66 mmol) obtained in Example 19 was dissolved in 10 ml of toluene, and while stirring the solution under nitrogen atmosphere on an ice water bath, a toluene solution (1.3 ml, 1.32 mmol) of 1.0 M
diethyl aluminum cyanide was added dropwise thereto. The 35 temperature of the mixture was raised to rooIrL temperature, and sti~ring was continued . Af ter disappearance of the ~ 21789~4 starting materials was confirmed, a 2 N sodium hydroxide aqueous solution was added to the mixture, and the mixture was extracted twice with each 2 0 ml of toluene . The residue obtained after the organic layer was washed with 5 water, dried (Na2~04) and concentrated was applied to silica gel column chromatography (chloroform: methanol =
30: 1) to give a cyano compound (20 mg, 9 %) from a desired fraction.
o LlcO ~
~ `CH=C(CN~CL!e2NEt2 UeO
NMR (250 MHz, CDCl3) ~i ppm: 1.11 (t, ~J=7.2Hz, 6H), 1.41 (s, 15 6~), 2.63 (q, J=7.1Hz, 4H), 3.94 (s, 3H), 3 97 (s, 3H), 6.92 (d, ~=8.4Hz, lH), 7.51 (dd, ~=8.3, l.9HZ, lH), 7.60 (s, 2H) .
m.p. 82 to 83 C, orange-tinted yellow plate crystal IR (Ksr) cm~l: 3424, 2969, 2824, 2214, 1660, 1597, 1582, 1518, 1426, 1273, 1157, 1020.
Example 31 YeO~XNEt 2 UeO~ CH=C(Clle2NEt~) N O
lleO
The ynone compound (500 mg, 1. 65 mmol) obtained in Example 19 and morpholine (150 mg, 1.65 mmol) were dissolved in 7 ml of methanol, and the mixture was stirred at room temper-ature overn~ght. After completion of the reaction, the residue obtained by concentrating the solvent under reduced pressure was applied to silica gel column chromatography 21 /89~4 ~n-hexane: ethyl acetate = 2: 1~ to give a desired compound (410 mg, 64 %) f~rom a desired fraction.
o 3~eO ~ e2~ ) N
UeO
H NMR (CDC13, 250 MHz) ~ ppm: 1.06 (t, .J=7.1Hz, 6H), 1.39 (s, 6H), 2.57 (q, J=7.2Hz, 4H), 3.76 to 3.82 (m, 8H), 3.92 (s, 3H), 3.94 (s, 3H), 5.86 (s, lH), 6.85 (d, J=8.3Hz, lH), 7.44 (dd, J=8.3, l.9Hz, lH), 7.53 (d, J=1.9Hz, lH) .
m.p. yellow oily substance IR (neat) cm~1: 3422, 2994, 2951, 2838, 2363, 1844, 1615, 1580~ 1505, 1462, 1410, 1390, 1362, 1260, 1204, 1154, 1125, 1026. : -Example 32 In the same manner as in Example 31, :~rom the ynone com-20 pound obtained in Example 19 and monomethylamine, a ~inylamine compound (yield: 95 %) o .Ue~ H=~ Ie2~1E~2~N~le was ~ obtained .
lH NMR (CDCl3, 250 MHz) ~ ppm: 1.09 (t, 7.1Hz, 6H), 1.38 (s, 6H), 2.57 (q, J=7.1Hz, 4H), 3.52 (d, J=5.2Hz, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 5.77 (s, lH), 6.85 (d, J=8 4Hz, lH), 7.42 (dd, J=8.3, 1.7Hz, lH), 7.52 (d, J=1.8Hz, lH) .
Colorless oily state IR (neat) cm~1: 2971, 2836, 2045, 1738, 1609, 1557, 1507, 35 146g, 1391, 1300,- 1211, 1175, 1144, 1026, 774 .
2~7~f~
.
Exampl e 3 3 ~--re C 0 ~ C O ~T ~I p n 1) Li~ Pr)~
~eO ~HQ O
I!eD ~1~
~OJ ` ~aNHPh ~ ~InO~ b{eO ~' 10 A tetrahydrofuran solution (100 ml) of propiolic acid ~5.64 g, 80 mmol) was stirred on an ice bath, and triethylamine (13 4 ml, 96 mnol), aniline (8.0 ml, 88 mmol) and phos-phorus oxychloride (8.2 ml, 88 mmol) wére added thereto.
The mixture was stirred at rool}L tempera~ure overnight, and to the reaction mixture was added water under ice cooling.
Under reduced pressure, the solvent was removed by evapora-tion, and the residue was extracted with ethyl acetate (50 ml x 2) After the extract was conce~trated, the residue was purlfied by silica gel column chromatography (develop-ing solution: chloroform/ethyl acetate = 2/1) to obtain an anilide compound (5.58 g, yield: 48 %~ Under nitrogen atmosphere, a tetrahydrofuran solution (40 ml) of the anilide compound (1. 60 g, ll . O mmol) was cooled to -70 C, and while stirring the solution, a 2 M lithium diisopropyl amide cyclohexane solution (11.6 ml, ~3 1 mmol) was slowly added dropwise thereto. After the mixture was stirred for 1 hour, 3,4-dimethoxybenzaldehyde (1.83 g, 11.0 mnol) was added to thereto.. The temperature of the reaction mixture was raised to room temperature over 1 hour, the mixture was 30 subseouently cooled to.O C, and then water (10 ml) was added thereto to terminate the reaction . Af ter the solvent was removed by evaporation under reduced pressure, water (30 ml) was added to the residue, and the product was extracted with ethyl acetate (50 ml). After the extract 35 was dried (anhydrous sodium sulfate) and concentrated, the r~sidue obtained was purified by silica gel column chroma-tography (developing solution: chloroform~e~hyl acetate =4/1) to give an alcohol compound (1.22 g, 36 %~ which was an adduct. This alcohol compound (1.20 g, 3.9 mmol) was subjected to an oxidation reaction by the same method as in 5 Exa~[ple 14, and the obtained crude product was applied to silica gel column chromatography (developing solution = n-hexane/chloroform/ethyl acetate = 1/1/1) and then rinsed with ether-hexane and collected by filtration to give the desired above-mentioned ketone compound (630 mg, yield: 53 10 ~).
H NMR (250 ~, CDCl3) ~ ppm: 3.93 and 3.97 (2s, 6H), 6.75 (d, J=8.5Hz, lH), 7.19 (t, ~J=7.6Xz, lH), 7.37 (m, 12H), 7.54 (d, .J-1.8Hz, lH), 7.60 (d, J=8 2Hz, 2H), 7.83 (dd, 3=1.9~ 8.5Hz, lH), 8.36 (brs, lH) .
Shape: pale orange powder m.p. 140 to 142 C
IR (K~3r) cm~1: 3324, 1680, 1630, 1599, 1584, 1545, 1510, 1462, 1442, 1420, 1321, 1271, 1171, 1144, 1020, 874, 760.
~eOx~ ~hSH G) ` CD~i~Ph ~ : ~
MeO~ CH=C (C01~'~Ph) SPh ~leO
~ CH= C (CONhPh) ~0 ?.(eO
35 The above ketone compound (200 mg, 0.65 mmol) was dissolved in 5 ml of dichloromethane, 70 ml (0 65 mmol) of thiophenol and one drop of piperidine were added dropwise thereto, and the mixture was stirred at room temperature overnight. The residue obtained after the solvent was concentrated was applied to silica gel column chromatography (n-hexane:
5 ethyl acetate = 4: 1) to give a sulfide compound (10 mg, 4 %) and an amine compound (30 mg, 12 %) from desired fractions .
Sul f ide compound C~{=C(CQhl~P~)~Ph ~D
lH NMR (25Q MHz, CDCl3) ~i ppm: 3.95 (s, 3H), 3.97 (s, 3H), 6.92 (d, J=8 2HZ, lH), 7.06 to 7.32 (m, 8H), 7.47 (d, J=7.0Hz, 2H), 7.58 (s, lH), 7.68 (d, J=9 8HZ, lH), 7.83 (brs, lH), 7.89 (s, lH) .
2 0 Amine con~nd O
~ C~l=C(~D~3~Ph)l;O
H NME~ (250 MHZ, CDC13) ~ ppm: 1.71 (brs, 6H), 4.33 (brs, 4H), 3.89 (s, 3H), 3.92 (s, 3H), 5.90 (s, lH), 6,84 (d, J=8 3HZ, lH), 7 13 ( t, J=7.4Hz, lH), 7.35 ( t, J=8.lHz, 2H), 7 47 to 7 . 54 (m, 3H), 7 . 65 (d, J=8 3Hz, 2H) IR (Ksr) cm~1: 3345, 2938, 1686~ 1599:, 1545, 1508, 1439, 1254, 1165, 1022, 870, 758 m.p. 196 to 198 'C, colorless needle crystal Exampl e 3 4 2~789~4 D
~o J~ PhSH
L~eO/~ ~ ~E' *
o ~le O J~ C ~S~h~ = C~CIIe2 NE ~ 2 lleO
o ~ h=c(sph)~e2~t2 l~e~
The ynone compound (500 mg, 1.65 mmol) obtained in Example 19, thiophenol (180 mg, 1.65 mmol) and a catalytic amount of piperidine were dissolved in 5 ml of ether, and the mixture was stirred under nitrogen atmosphere at room 20 temperature for 7 hours. After disappearance of the starting materials was confirmed, the residue given by concentrating the solvent was applied to silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain an ~x-sulfide compound (430 mg, 63 96) and a 3-sulfide com-pound (170 mg, 25 %) from desired fractions.
~-Sulfide compound o 3 0 ~ C (S~h) =~HCLle2 .~1E t 2 H NM~ (250 MHz, CDCl3) ~ ppm: 1.13 (t, J=7.1Hz, 6H), 1.48 ~s, 6H), 2.68 ~q, J=7.1Hz, 4H), 3.82 ~s, 3H), 3.93 ~s, 3H), 6.66 ~s~; lH), 6.78 ~d, J=8.5Hz, lH), 7.01 (s, 6H), 7.34 (d, J=8 . 5Hz, lH) .
.
!3-- Sul f ide compound ~leO~ c~ sph)~2N~l2 ~leO
H NMR (250 MHz, CDCl3) ~ ppm: 1 01 (t, J=7 1Hz, 6H), 1.44 (s, 6H), 2.56 (c, ~=7.1Hz, 4H), 3.89 (s, 3H), 3.91 (s, 3H~, 5.69 (s, ~H), 6.82 (d, ~J=8 2Hz, lH), 7 33 to 7.38 (m, SH), 7 57 (dd, ~=8 1, 1 7Hz, 2H) Exarnple 35 ~leO~ ~(~Ph)=C~lC~e~2NE12 ~$
lleD
o 2 t ~le~(SDPh~ C~e2NEt2 ~EC D
~0 T~le c~-sulfide compound (100 mg, 0 24 mmol) obtained in Example 34 was dissolved in 10 ml of chloro~orm, and while 25 stirring the solution on an ice water bath, 80 mg of mCPBA
(purity: 55 %) was added thereto The temperature of the mixture was ra~séd to room temperature, and stirring was continued for 2 hours After disappea~nce of the starting mater~als were c~nfirTn~rl, a saturated sodium hydrogen 30 carbonate agueous solution (0.24 mmol) was added to the mixture, and the mixture was extracted twice with each 20 ml of chloroform. The residue obtained by washing the organic layer with water, drying it (~a2S04) and concen-trating it was applied to sllica gel chromatography (n-35 hexane :- ethyl acetate = 2: 1) to give a sulfoxide com-pound (50 mg, 48 %).
~ 2l7~4 40 mg of the compound obtained here was dissolved in 10 ml of diethyl ether, a 4 N-hydrochloric acid ethyl acetate solution (O . 2 ml) was added dropwise thereto under nitrogen atmosphere on an ice bath, and the mixture was stirred at 5 the same temperature for lO minutes. The produced precipi-tates were collected by filtration, dried and suspended in ethyl acetate-diethyl ether (1/5) . After stirring for 10 minutes, the precipitates were collected by filtration to give hydrochloride of a desired sulfoxide (30 mg, 69 %).
IleO~(SOPh)=C~lC11e2~1Et2 HC~
lS1H NMR (250 MHz, CDCl3) ~ ppm: 1.21 to 1 76 (m, 12H), 3.23 to 3.86 (m, 4H), 4.02 (s, 3H), 4.06 (s, 3H), 7.05 (d, J=8 . ~Hz , lH), 7 . 57 to 7 . 75 (m, 6H), 8 . 01 (dd, J=8 . 5 , 2 . 0Hz , lH), 8.43 (s, lH), 10.49 (brs, lH) .
m.p. yellow oily state 20 IR (KBr) cm~1: 3409, 3003, 1649, l582, 1512, 1424, 1304, 1265, 1173, 1152, 1020, 984, 754.
Example 36 25 l~eO~ Cl~-C(SPh)C~(e2N~t2 l~eO
o lleO~il=C(~OPh) C~le2NEt 2 ~C ~?
I~eO
From the p-sulfide compound ~80 mg, O.19 mmol) obtained in 35 Example 38, hydrochloride of sulfoxide (60 mg, overall 2178q~4 yield: 68 ~) was obtained by the same method as in Example 35 .
o ~H=C(SDPh)CUr2~Et ~ HC
~1~0 lH ~MR (250 MHz, CDC13) ~ ppm: 1.51 to 1.84 (m, 12H), 2.96 to 3.22 (m, 2H), 3.42 to 3.54 (m, lH), 3.80 to 3.98 (m, lH), 3.97 (s, 3H), 4.00 (s, 3H), 7.08 (d, J=8.4Hz, lH), 7.52 to 7.61 (m, 3H), 7.76 (s, lH), 7.87 (dd, J=8.2Hz, 2H), 8.39 (d, J=8.4Hz, lH), 9.62 (s, 1H), 11.10 (brs, lH) .
m.p. 110 to 112 'C, colorless powder Br) cm~l: 3407, 2986, 1628, 1593, 1572, 1514, 1444, 1422, 1275, 1219, 1154, 1076, 1015, 872, 768.
Test example In order to evaluate the tyrosine kinase inhibiting activ-ity and the cancer cell growth inhibiting activity of the compound of the present invention, tests were carried out in a partially purified human EGF (epithelial cell growth factor) receptor tyrosine kinase activity measuring system and a cell culture system using human cancerous cells.
(Tyrosine kinase inhibiting activity) (Measurement method) The tyrosine kinase inhibiting activity was measured by using an EGF receptor which was partially purified from an A431 cell line derived from human squamous cell carcinoma and by improving the tyrosine kinase activity measurement method described in Linda J. Pike et al., Proceedings of the National Academy of Sciences af the U.S A. 79, 1443 ( 1982 ) .
-2 ~ 7~ ~ 4 The detailed method is as described below.
A431 cells were cultured in a Dulbecco modified Eagle's medium (DMEM) containing 10 % fetal calf serum ~FCS), at 37 5 C under 5 % carbonic acid gas. The cells were homogenized in a solution containing 10 mM N-2-hydroxyethylpiperazino-N~-2-ethanesulfonic acid (Hepes) buffer (pH 7.4), 0.25 M
saccharose and 0.1 mM EDTA and then centrifuged at 3000 g for 5 minutes. Further, a supernatant thereof was centri-fuged at 10000 x g for 30 minutes to obtain an A431 cell membrane fraction, and this fraction was provided for measurement as a partially purified EGF receptor which was an enzyme source 15 To a reaction mixture of the above-mentioned A431 cell rn~rn~r~nf~ fraction (10 to 15 ,ug), a 15 mM Hepes buffer (pH
7.7), 2 mM MnC12, 10 ~LM ZnS04, 50 IIM Na3V04 and a sample dissolved in dimethylsulfoxide (DMSO) (final concentration:
1 % DMSO) was added 100 ng of EGF, and then 75 ,ug of a 20 synthetic substrate RR-SRC peptide (a peptide described in Sequence ~o. 1) and 10 IIM gamma-32P-adenosine triphosphoric acid (55 5 Ksq) were added thereto to start a reaction.
The volume at that time was 60 ,ul.
The reaction was carried out in ice for 30 minutes, and the reaction was terminated by adding 6 ,ul of 10 mg/ml bovine serum albumin and 25 1ll of 20 % trichloroacetic acid. The reaction mixture was left to stand in ice for 30 minutes.
Next, after the mixture was centrifuged at 5000 x g for 2 minutes, 40 111 of the supernatant was sampled and adsorbed to P81 phosphocellulose paper.
35 This was dipped in a 30 % acetic acid solution for 15 minutes to fix, washed by dipping in a 15 % acetic acid solution for 15 minutes (washing was repeated four times) and measured the count of 32p attached to P81 phosphocel-lulose paper by a lis~uid s~-;nt;ll~tion counter, and this value was defined as A.
At the same time, the counts of a reaction in which the sample tested was not added and a reaction in which both the sample and EGF were not added were measured and were defined as B and C, respectively.
T~le tyrosine kinase inhibiting rate is det~rm; nl~l by the following Eormula.
Inhibiting rate ~96) = (B-A/B-C) x 100 From the inhibiting rate obtained by changing the addition concentration of the sample, an IC50 value (50 96 inhibiting concentration) was calculated.
20 (Cancer cell growth inhibiting activity) (Measurement method) Ks cells of human rhinopharyngeal cancer retain EGF
25 receptor on cellular surfaces thereof excessively.
By using these KB cells, investigation of the effect of a sample on growth of cultured cancer cells was carried out by the following method.
2 . 5 x 103 cell/wel of l~s cells were sowed on a 96 well dish and cultured in a DMEM: F12 (1: l) medium containing 10 96 FCS, 50 U~ml penicillin and 50 llg/mi oE streptomycin, under conditions of 37 C and 5 96 carbonic acid gas for 1 day.
35 Thereafter, a sample dissolved in DMSO was added to the medium (DMSO Einal concentration: <0.1 96) and cultured 2~7~q~4 under the above conditions for 3 days. The sample and the medium were replaced every 24 hours.
The count of the number of living cells was determined by 5 colorimetric quantitation at two wavelengths of 550 nm and 650 nm using a MTT reagent by referring to the measurement method described in Michael C. Alley et al, Cancer Research ~8, 589 (1988), and the value was defined as a.
10 At the same time, the count of the number of living cells when the sample was not added was also measured, and the value was def ined as b .
The cell growth inhibiting rate was de~,orm; n~ by the 15 following formula.
Inhibiting rate (%) = (b-a) /b x 100 From the inhibiting rate obtained by changing the addition 20 concentration of the sample, an IC50 value (50 % inhibiting concentration) was calculated.
The above results are shown in Table-2.
? 1 78 9 1 4 .
Table - 2 Tyrosine kinase Cancer cell growth Compound inhibiting activity inhibiting activ-(NO-) (ICso, ,UM) ity (ICso, ~
0.34 0.62 26 0.86 1.9 29 9 .4 3 . 9 97 8.2 2.6 335 27 . 9 3 . 1 278 1 . 7 0 . 95 2~3 1.1 0.23 350 1.4 0 57 3 52 0 . 47 0 . 63 349 5.8 2.0 29Q 5.0 0.83 327 27 . 3 5 . 0 253 ~ 38 0 . 42 Utilizability in industry The benzoylethylene derivative of the present invention has potent tyrosine kinase inhibiting activity and cancer cell ~rowth inhibiting activity, and the tyrosine kinase inhibitor of the present invention i5 useful as a carcino-10 static agent.
Sequence listing Sequence No: 1 Length of sequence: 13 15 Type of sequence: amino acid Topology: linear ~ind of seauence: pep~ide Sequence Arg Arg Leu Ile Glu Asp Ala Glu Tyr Ala Ala Arg Gly
Claims (14)
1. A benzoylethylene derivative represented by the following formula (I):
(I) [wherein, in the above formula (I), R1 to R5 each indepen-dently represent (1) a hydrogen atom, (2) -OR9 [wherein R9 represents a hydrogen atom or a C1-C5 alkyl group which may be substituted by a halogen atom or a phenyl group.], (3) a halogen atom, (4) a C1-C5 alkyl group which may be substi-tuted by a halogen atom, (5) -NR10R11 (wherein R10 and each independently represent a hydrogen atom, a phenyl group, a C1-C5 alkyl group which may be substituted by a phenyl group, a benzoyl group or an acetyl group.), (6) -SOpR12 (wherein p represents 0, 1 or 2, and R12 represents a C1-C5 alkyl group or a phenyl group.), (7) a cyano group or (8) a nitro group, or represent a C1-C3 oxyalkylene group having 1 or 2 oxygen atoms by combining the adjacent substituents.
R6 and R7 each independently represent (1) a hydrogen atom, (2) a cyano group, (3) a halogen atom, (4) a C1-C5 alkyl group which may be substituted by a halogen atom, (5) -NR13R14 (wherein R13 and R14 each independently represent a hydrogen atom or a C1-C5 alkyl group, or are combined together to form a C3-C6 alkylene group which may be inter-vened by -O-.) or (6) -SOqR15 (wherein q represents 0, 1 or 2, and R15 represents a C1-C5 alkyl group which may be substituted by a halogen atom, a thienyl group or a phenyl group which may be substituted by a halogen atom, a C1-C5 alkyl group, a cyano group, a nitro group or a C1-C5 alkoxy group.).
R8 represents (1) a cyano group, (2) -COR16 [wherein R16 represents a C1-C5 alkoxy group which may be substi-tuted by a phenyl group, or -NR17R18 (wherein R17 and R18 each independently represent a hydrogen atom or a phenyl group which may be substituted by a halogen atom or a C1-C5 alkyl group.).] or (3) -CR22R23X {wherein R22 and R23 each independently represent a hydrogen atom or a C1-C5 alkyl group, or are combined together to represent a C3-C6 alkyl-ene group which may be substituted by a C1-C5 alkyl group, and X represents a hydroxyl group or -NR24R25 [wherein R24 and R25 each independently represent (a) a hydrogen atom, (b) a phenyl group which may be substituted by a halogen atom or a C1-C5 alkyl group, (c) a C1-C5 alkyl group which may be substituted by a phenyl group or a C1-C5 alkylamino group, (d) a C3-C8 cycloalkyl group or (e) -COR26 (wherein R26 represents a C1-C5 alkyl group, a phenyl group or a C1-C5 alkoxy group which may be substituted by a phenyl group.), or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27-(wherein R27 represents a hydrogen atom or a C1-C5 alkyl group.), or a C3-C6 alkylene group which may be substituted by a C1-C5 alkyl group.].}. Provided that when R6 and R7 represent hydrogen atoms simultaneously, R16 does not represent -NR17R18.]
or a salt thereof.
(I) [wherein, in the above formula (I), R1 to R5 each indepen-dently represent (1) a hydrogen atom, (2) -OR9 [wherein R9 represents a hydrogen atom or a C1-C5 alkyl group which may be substituted by a halogen atom or a phenyl group.], (3) a halogen atom, (4) a C1-C5 alkyl group which may be substi-tuted by a halogen atom, (5) -NR10R11 (wherein R10 and each independently represent a hydrogen atom, a phenyl group, a C1-C5 alkyl group which may be substituted by a phenyl group, a benzoyl group or an acetyl group.), (6) -SOpR12 (wherein p represents 0, 1 or 2, and R12 represents a C1-C5 alkyl group or a phenyl group.), (7) a cyano group or (8) a nitro group, or represent a C1-C3 oxyalkylene group having 1 or 2 oxygen atoms by combining the adjacent substituents.
R6 and R7 each independently represent (1) a hydrogen atom, (2) a cyano group, (3) a halogen atom, (4) a C1-C5 alkyl group which may be substituted by a halogen atom, (5) -NR13R14 (wherein R13 and R14 each independently represent a hydrogen atom or a C1-C5 alkyl group, or are combined together to form a C3-C6 alkylene group which may be inter-vened by -O-.) or (6) -SOqR15 (wherein q represents 0, 1 or 2, and R15 represents a C1-C5 alkyl group which may be substituted by a halogen atom, a thienyl group or a phenyl group which may be substituted by a halogen atom, a C1-C5 alkyl group, a cyano group, a nitro group or a C1-C5 alkoxy group.).
R8 represents (1) a cyano group, (2) -COR16 [wherein R16 represents a C1-C5 alkoxy group which may be substi-tuted by a phenyl group, or -NR17R18 (wherein R17 and R18 each independently represent a hydrogen atom or a phenyl group which may be substituted by a halogen atom or a C1-C5 alkyl group.).] or (3) -CR22R23X {wherein R22 and R23 each independently represent a hydrogen atom or a C1-C5 alkyl group, or are combined together to represent a C3-C6 alkyl-ene group which may be substituted by a C1-C5 alkyl group, and X represents a hydroxyl group or -NR24R25 [wherein R24 and R25 each independently represent (a) a hydrogen atom, (b) a phenyl group which may be substituted by a halogen atom or a C1-C5 alkyl group, (c) a C1-C5 alkyl group which may be substituted by a phenyl group or a C1-C5 alkylamino group, (d) a C3-C8 cycloalkyl group or (e) -COR26 (wherein R26 represents a C1-C5 alkyl group, a phenyl group or a C1-C5 alkoxy group which may be substituted by a phenyl group.), or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27-(wherein R27 represents a hydrogen atom or a C1-C5 alkyl group.), or a C3-C6 alkylene group which may be substituted by a C1-C5 alkyl group.].}. Provided that when R6 and R7 represent hydrogen atoms simultaneously, R16 does not represent -NR17R18.]
or a salt thereof.
2. The compound according to Claim 1, wherein R8 is a cyano group or -CR22R23X (wherein R22 and R23 each independ-ently represent a hydrogen atom or a C1-C5 alkyl group, or are combined together to represent a C3-C6 alkylene group which may be substituted by a C1-C5 alkyl group, and X
represents a hydroxyl group or -NR24R25 [wherein R24 and R25 each independently represent (a) a hydrogen atom, (b) a phenyl group which may be substituted by a halogen atom or a C1-C5 alkyl group, (c) a C1-C5 alkyl group which may be substituted by a phenyl group or a C1-C5 alkylamino group, (d) a C3-C8 cycloalkyl group or (e) -COR26 (wherein R26 represents a C1-C5 alkyl group, a phenyl group or a C1-C5 alkoxy group which may be substituted by a phenyl group.), or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27- (wherein R27 represents a hydrogen atom or a C1-C5 alkyl group.), or a C3-C6 alkylene group which may be substituted by a C1-C5 alkyl group.].}.
represents a hydroxyl group or -NR24R25 [wherein R24 and R25 each independently represent (a) a hydrogen atom, (b) a phenyl group which may be substituted by a halogen atom or a C1-C5 alkyl group, (c) a C1-C5 alkyl group which may be substituted by a phenyl group or a C1-C5 alkylamino group, (d) a C3-C8 cycloalkyl group or (e) -COR26 (wherein R26 represents a C1-C5 alkyl group, a phenyl group or a C1-C5 alkoxy group which may be substituted by a phenyl group.), or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27- (wherein R27 represents a hydrogen atom or a C1-C5 alkyl group.), or a C3-C6 alkylene group which may be substituted by a C1-C5 alkyl group.].}.
3. The compound according to Claim 1, wherein R7 is a hydrogen atom, a cyano group, a C1-C5 alkyl group or -SOqR15 (wherein q represents 0, 1 or 2, and R15 represents a C1-C5 alkenyl group which may be substituted by a halogen atom, a thienyl group or a phenyl group which may be substituted by a halogen atom, a C1-C5 alkyl group, a cyano group, a nitro group or a C1-C5 alkoxy group.), and R8 is a cyano group or -CR22R23X {wherein R22 and R23 each indepen-dently represent a hydrogen atom or a C1-C5 alkyl group, or are combined together to represent a C3-C6 alkylene group which may be substituted by a C1-C5 alkyl group, and X
represents a hydroxyl group or -NR24R25 [wherein R24 and R25 each independently represent (a) a hydrogen atom, (b) a phenyl group which may be substituted by a halogen atom or a C1-C5 alkyl group, (c) a C1-C5 alkyl group which may be substituted by a phenyl group or a C1-C5 alkylamino group, (d) a C3-C8 cycloalkyl group or (e) -COR26 (wherein R26 represents a C1-C5 alkyl group, a phenyl group or a C1-C5 alkoxy group which may be substituted by a phenyl group.), or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27- (wherein R27 represents a hydrogen atom or a C1-C5 alkyl group.), or a C3-C6 alkylene group which may be substituted by a C1-C5 alkyl group.}.}.
represents a hydroxyl group or -NR24R25 [wherein R24 and R25 each independently represent (a) a hydrogen atom, (b) a phenyl group which may be substituted by a halogen atom or a C1-C5 alkyl group, (c) a C1-C5 alkyl group which may be substituted by a phenyl group or a C1-C5 alkylamino group, (d) a C3-C8 cycloalkyl group or (e) -COR26 (wherein R26 represents a C1-C5 alkyl group, a phenyl group or a C1-C5 alkoxy group which may be substituted by a phenyl group.), or are combined together to represent a C3-C6 alkylene group which may be intervened by -O- or -NR27- (wherein R27 represents a hydrogen atom or a C1-C5 alkyl group.), or a C3-C6 alkylene group which may be substituted by a C1-C5 alkyl group.}.}.
4. The compound according to Claim 1, wherein R1 and R5 are hydrogen atoms, R2, R3 and R4 each independently are a hydrogen atom or -OR9' (wherein R9' represents a C1-C5 alkyl group.), or R2 and R3 are combined to be C1-C3 oxyalkylene having 1 or 2 oxygen atoms, R6 is a hydrogen atom or a C1-C5 alkyl group, R7 is a hydrogen atom, a cyano group, a C1-C5 alkyl group or -SOq'R15' (wherein q' represents 2, and R15' represents a thienyl group or a phenyl group which may be substituted by a C1-C5 alkyl group or a nitro group.), and R8 is a cyano group or -CR22'R23'X' {wherein R22' and R23' each independently represent a hydrogen atom or a C1-C5 alkyl group, and X' represents -NR24'R25' (wherein R24' and R25' each independently represent a C1-C5 alkyl group or are combined together to represent a C3-C6 alkylene group which may be substituted by a C1-C5 alkyl group.).}.
5. The compound according to Claim 1, wherein R1, R4 and R5 are hydrogen atoms, R2 and R3 each independently are -OR9' (wherein R9' represents a C1-C5 alkyl group.), R6 is a hydrogen atom, R7 is -SOq'R15" (wherein q' represents 2, and R15" represents a phenyl group which may be substituted by a C1-C5 alkyl group or a nitro group.), and R8 is -CR22"R23"X" {wherein R22" and R23" each independently represent a C1-C5 alkyl group, and X" represents -NR24"R25"
(wherein R24" and R25" each independently represent a C1-C5 alkyl group.).}.
(wherein R24" and R25" each independently represent a C1-C5 alkyl group.).}.
6. The compound according to Claim 1, wherein R1, R4 and R5 are hydrogen atoms, R2 and R3 are methoxy groups, R6 is a hydrogen atom, R7 is a phenylsulfonyl group, and R8 is -C(CH3)2N(C2H5)2.
7. A tyrosine kinase inhibitor which comprises the com-pound according to any one of Claims 1 to 6 as an active ingredient.
8. A medical composition which comprises the compound according to any one of Claims 1 to 6 and a pharmaceutical-ly acceptable carrier.
9. The medical composition according to Claim 8 for treating cancer.
10. The medical composition according to Claim 8 for suppressing cancer cell growth.
11. The medical composition according to Claim 8 for treating arteriosclerosis.
12. The medical composition according to Claim 8 for inhibiting platelet aggregation.
13. The medical composition according to Claim 8 for immunosuppression.
14. The medical composition according to Claim 8 for suppressing inflammation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17535794 | 1994-07-27 | ||
| JP6/175357/1994 | 1994-07-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2178914A1 true CA2178914A1 (en) | 1996-02-08 |
Family
ID=15994665
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002178914A Abandoned CA2178914A1 (en) | 1994-07-27 | 1995-07-25 | Benzoylethylene derivative |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US5789448A (en) |
| EP (1) | EP0721930A4 (en) |
| CA (1) | CA2178914A1 (en) |
| WO (1) | WO1996003364A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100270410B1 (en) * | 1997-03-06 | 2000-11-01 | 성재갑 | Novel 1,3-diphenylpropane derivative having inhibitive activity against tyrosinase and process for preparation thereof |
| US7012095B2 (en) * | 2000-04-13 | 2006-03-14 | Hsc Research And Development Limited | Compounds for modulating cell proliferation |
| US20030186221A1 (en) * | 2002-04-02 | 2003-10-02 | Lockhart David J. | Phage display affinity filter and forward screen |
| WO2003090686A2 (en) * | 2002-04-25 | 2003-11-06 | University Of Connecticut Health Center | Using heat shock proteins to improve the therapeutic benefit of a non-vaccine treatment modality |
| CA2560584A1 (en) * | 2004-03-26 | 2005-10-06 | Hsc Research And Development Limited Partnership | Novel compounds for modulating cell proliferation |
| CN102816067A (en) * | 2011-06-09 | 2012-12-12 | 中国医学科学院医药生物技术研究所 | 4-hydroxybenzoylacrylic acid derivative, preparation method thereof and application |
| JP6533997B2 (en) * | 2014-12-26 | 2019-06-26 | 株式会社ヤクルト本社 | Compound having ZNF143 inhibitory activity and use thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3864344A (en) * | 1971-04-02 | 1975-02-04 | Cassella Farbwerke Mainkur Ag | 3-(Benzoyl)-2-(4{40 -anilino carbonyl or benzoxy-alkyl piperazino)-propionitriles |
| CS201121B1 (en) * | 1976-07-29 | 1980-10-31 | Viktor Zikan | Beta-4-pentoxybenzoyl-alpha,alpha'-dialoxy-propionic acid,esters thereof and process for their preparation |
| CA1151164A (en) * | 1978-01-13 | 1983-08-02 | Atsuyuki Kojima | Conjugated ketone compounds and their production and use |
| JPS63130564A (en) * | 1986-11-19 | 1988-06-02 | Denki Kagaku Kogyo Kk | Production of benzoylacrylic acid esters |
| CA2080554A1 (en) * | 1991-10-15 | 1993-04-16 | Mitsubishi Chemical Corporation | Styrene derivatives |
| US5618829A (en) * | 1993-01-28 | 1997-04-08 | Mitsubishi Chemical Corporation | Tyrosine kinase inhibitors and benzoylacrylamide derivatives |
| TW312688B (en) * | 1993-08-02 | 1997-08-11 | Mitsubishi Chem Corp |
-
1995
- 1995-07-25 EP EP95926022A patent/EP0721930A4/en not_active Withdrawn
- 1995-07-25 US US08/619,519 patent/US5789448A/en not_active Expired - Fee Related
- 1995-07-25 WO PCT/JP1995/001475 patent/WO1996003364A1/en not_active Application Discontinuation
- 1995-07-25 CA CA002178914A patent/CA2178914A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP0721930A4 (en) | 1997-07-16 |
| US5789448A (en) | 1998-08-04 |
| WO1996003364A1 (en) | 1996-02-08 |
| EP0721930A1 (en) | 1996-07-17 |
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